• Loading stock data...

Glutamate as a Neurotransmitter

An overview by Niels Chr. Danbolt

For more references and more information, see: Danbolt, 2001: Prog. Neurobiol. 65, 1-105.



Outside the community of biomedical scientists, glutamate is probably best known as “monosodium glutamate” or “MSG” which is used as a flavor or taste enhancer in food. It is usually available together with other food additives and spices in most large food stores. Some people may also have heard the term “Chinese restaurant syndrome” which is a sudden fall in blood pressure with subsequent fainting after ingestion of very spicy food. Excessive use of MSG has been suggested to be the cause, but this is controversial. The use of glutamate as a food additive, however, is not the reason for the enormous scientific interest in glutamate.

Glutamate is the major excitatory transmitter in the brain

The main motivation for the ongoing World Wide research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning.

Glutamate is toxic, not in spite of its importance, but because of it

Glutamate does not only mediate a lot of information, but also information which regulates brain development and information which determines cellular survival, differentiation and elimination as well as formation and elimination of nerve contacts (synapses). From this it follows that glutamate has to be present in the right concentrations in the right places for the right time. Both too much and too little glutamate is harmful. This implies that glutamate is both essential and highly toxic at the same time.

It took a long time to realize that glutamate is a neurotransmitter

It may sound astonishing, but it took the scientific community a long time to realize that glutamate is a neurotransmitter although it was noted already 70 years ago that glutamate is abundant in the brain and that it plays a central role in brain metabolism. Ironically, the reason for the delay seems to have been its overwhelming importance. Brain tissue contains as much as 5 – 15 mmol glutamate pr kg, depending on the region, more than of any other amino acid. Glutamate is one of the ordinary 20 amino acids which are used to make proteins and takes parts in typical metabolic functions like energy production and ammonia detoxification in addition to protein synthesis. It was hard to believe that a compound with so many functions and which is present virtually everywhere in high concentrations could play an additional role as transmitter.

How glutamate works as a transmitter

Like other signaling substances (neurotransmitters and hormones) the signaling effect of glutamate is not dependent on the chemical nature of glutamate, but on how cells are programmed to respond when exposed to glutamate. Only cells with glutamate receptor proteins (“glutamate receivers”) on their surfaces are sensitive to glutamate. Glutamate exerts its signaling function by binding to and thereby activating these receptor proteins. Several subtypes of glutamate receptors have been identified: NMDA, AMPA/kainate and metabotropic receptors (mGluR).

Although the individual receptor subtypes show specific (restricted) localizations, glutamate receptors of one type or another are found virtually everywhere. Most of the nerve cells, and even glial cells, have glutamate receptors.

Glutamate must be kept inside the cells (intracellularly)

At first glance this looks like an impossible system. A closer look, however, reveals that glutamate is not present everywhere. It is almost exclusively located inside the cells. The intracellular location of some 99.99 % of brain glutamate is the reason why this system can work. This is essential because glutamate receptors can only be activated by glutamate binding to them from the outside. Hence, glutamate is relatively inactive as long as it is intracellular.

The volume of brain cells and of the meshwork formed by their intermingled extensions, constitute about 80 % of brain tissue volume. This network is submerged in a fluid, the extracellular fluid which represents the remaining 20 % of brain tissue volume. The normal (resting) concentration of glutamate in this fluid is low, in the order of a few micromolar. In contrast, the glutamate concentration inside the cells is several thousand times higher, at around 1 – 10 millimolar. The highest glutamate concentrations are found in nerve terminals and the concentration inside synaptic vesicles may be as high as 100 millimolar.

The glutamate transporters remove glutamate from the extracellular fluid

It follows from the description above that the mechanisms which can maintain low extracellular concentrations of glutamate are essential for brain function. The only (significant) mechanism for removal of glutamate from the extracellular fluid is cellular uptake of glutamate; the so called “glutamate uptake”. This uptake is mediated by a family of special transporter proteins which act as pumps. These proteins bind glutamate, one molecule at the time, and transfer them into the cells. In agreement with the abundance of glutamate and the ubiquity of glutamate receptors, brain tissue displays a very high glutamate uptake activity. This was noted already in 1949, although its true importance was not recognized until after the excitatory action of glutamate was discovered in the 1950s and 1960s.

Glutamate is taken up into both glial cells and nerve terminals. The former is believed to be the more important from a quantitative point of view. Glutamate taken up by astroglial cells is converted to glutamine. Glutamine is inactive in the sense that it cannot activate glutamate receptors, and is released from the glial cells into to extracellular fluid. Nerve terminals take up glutamine and convert glutamine back to glutamate. This process is referred to as the glutamate-glutamine, and is important because it allows glutamate to be inactivated by glial cells and transported back to neurons in an inactive (non-toxic) form.

Types of glutamate transporting proteins

A variety of transporters with affinity for glutamate

The mammalian genome contains five genes encoding glutamate (excitatory amino acid) transporters (for review see: Danbolt, 2001). These transporters are referred to as GLAST (EAAT1; slc1a3), GLT1 (EAAT2; slc1a2), EAAC1 (EAAT3; slc1a1), EAAT4 (slc1a6) and EAAT5 (slc1a7).

# EAAT2/GLT1 is the most important subtype in the mature brain. It represents about 1 % of total adult brain protein (Lehre and Danbolt, 1998) and accounts for about 95 % of the total glutamate uptake activity in the forebrain (Haugeto et al., 1996; Tanaka et al., 1997). GLT1 is predominantly expressed in astrocytes (Danbolt et al., 1992; Levy et al., 1993; Rothstein et al., 1994; Lehre et al., 1995). However, it is also the transporter that is responsible for the uptake into glutamatergic nerve endings, at least in the hippocampus (Chen et al., 2004; Furness et al., 2008). About 10 % of the GLT1 protein in the young adult rat hippocampus CA1 is found in axon-terminals (Furness et al., 2008) where it accounts for all of the glutamate uptake by glutamatergic nerve terminals (Furness et al., 2008). GLT1 is not found in dendrites (Furness et al., 2008). The splice variant responsible for this uptake is the predominant isoform, namely GLT1a. GLT1b is not detected in neurons after all, but is present in astroglia together with most of GLT1a (Holmseth et al., 2009). The distributions of GLT1 and GLAST in man and rodents are similar (Melone et al., 2011), and the controversy in the literature is probably due to postmortem proteolysis (Li et al., 2012). GLT1 is expressed at low levels at birth and reaches (in the forebrain) 50 % of adult levels at around postnatal day 21 (P21; Ullensvang et al., 1997). In agreement with the importance of GLT1, GLT1 deficient mice get epileptic at around P21 and 50 % die of epilepsy before P30 (Tanaka et al., 1997).

# EAAT1/GLAST is selectively expressed in astrocytes in the brain (Lehre et al., 1995). The highest levels are found in the cerebellum, but forebrain levels are also substantial (Lehre and Danbolt, 1998). GLAST is also more abundant than GLT1 in the retina (Lehre et al., 1997) and in the inner ear (Furness and Lehre, 1997). Like GLT1, GLAST expression in the forebrain reaches 50 % of adult levels at around P21, but the increase is not quite as dramatic because GLAST is readily detectable already at birth (Ullensvang et al., 1997). GLAST deficient mice have some motor discoordination and increased susceptibility to cerebellar injury, but appear healthy and survive to high age (Watase et al., 1998). They also display exacerbation of noise-induced hearing loss (Hakuba et al., 2000) in agreement with the role of GLAST in the inner ear (Furness and Lehre, 1997)

# EAAT3/EAAC1 has been more difficult to localize in part because it has been difficult to get good antibodies (e.g. Holmseth et al., 2005). Another reason is that the expression levels are about 100 times lower than those of GLT1 (Holmseth et al., 2012). EAAC1 is selective for neurons, but is only targeted to the cell bodies and dendrites. It is not present in axon-terminals and not in astrocytes (Shashidharan et al., 1997; Holmseth et al., 2012). EAAC1 deficient mice develop dicarboxylic aminoaciduria in agreement with the role of EAAC1 in the kidneys, but no neurodegeneration the first 12 months (Peghini et al., 1997), but possibly at higher age because EAAC1 mediates neuronal cysteine uptake (Aoyama et al., 2006).

# EAAT4 is mostly in cerebellar Purkinje cells, but there is also some in the forebrain (Dehnes et al., 1998). The small amounts in the forebrain are present in a subpopulation of neurons (Massie et al., 2001; de Vivo et al., 2010). EAAT4 deficient mice have an even milder phenotype (Huang et al., 2004)

Glutamate Transporters

The glutamate transporters (Excitatory Amino Acid Transporters; EAATs) are indicated in red. These are found in the plasma membranes. The vesicular glutamate transporters (VGLUTs) pack glutamate into synaptic vesicles (for review see: Danbolt, 2001)​

• 1Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1105, Blindern, N-0317, Oslo, Norway.

Glutamate uptake:


Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer’s disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.

High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance.

Rauen T1, Taylor WR, Kuhlbrodt K, Wiessner M.

Author information

• 1MPI für Hirnforschung, Abteilung für Neuroanatomie, Deutschordenstr. 46, D-60528 Frankfurt/M., Germany. rauen@mpih-frankfurt.mpg.de


Glutamate is the major excitatory neurotransmitter of the mammalian retina and glutamate uptake is essential for normal transmission at glutamatergic synapses. The reverse transcriptase-polymerase chain reaction (RT-PCR) has revealed the presence of three different high-affinity glutamate transporters in the rat retina, viz. GLAST-1, GLT-1 and EAAC-1. No message has been found in the retina for EAAT-4, a transporter recently cloned from human brain. By using membrane vesicle preparations of total rat retina, we show that glutamate uptake in the retina is a high-affinity electrogenic sodium-dependent transport process driven by the transmembrane sodium ion gradient. Autoradiography of intact and dissociated rat retinae indicates that glutamate uptake by Müller glial cells dominates total retinal glutamate transport and that this uptake is strongly influenced by the activity of glutamine synthetase. RT-PCR, immunoblotting and immunohistochemistry have revealed that Müller cells express only GLAST-1. The Km for glutamate of GLAST-1 is 2.1+/-0.4 microM. This study suggests a major role for the Müller cell glutamate transporter GLAST-1 in retinal transmitter clearance. By regulating the extracellular glutamate concentration, the action of GLAST-1 in Müller cells may extend beyond the protection of neurons from excitotoxicity; we suggest a mechanism by which Müller cell glutamate transport might play an active role in shaping the time course of excitatory transmission in the retina.

Molecular pharmacology of glutamate transporters, EAATs and VGLUTs.

Shigeri Y1, Seal RP, Shimamoto K.

Author information

• 1National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorigaoka, Ikeda, Osaka 563-8577, Japan. yasushi.shigeri@aist.go.jp


L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer’s disease, HIV-associated dementia, Huntington’s disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.

The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes.

Bridges RJ1, Esslinger CS.

Author information

• 1Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Science, The University of Montana, Missoula, MT 59812, USA. richard.bridges@umontana.edu


L-glutamate serves as the primary excitatory neurotransmitter in the mammalian CNS, where it can contribute to either neuronal communication or neuropathological damage through the activation of a wide variety of excitatory amino acid (EAA) receptors. By regulating the levels of extracellular L-glutamate that have access to these receptors, glutamate uptake systems hold the potential to effect both normal synaptic signaling and the abnormal over-activation of the receptors that can trigger excitotoxic pathology. Among the various membrane transporters that are capable of translocating this dicarboxylic amino acid, the majority of glutamate transport in the CNS, particularly as related to excitatory transmission, is mediated by the high-affinity, sodium-dependent, excitatory amino acid transporters (EAATs). At least 5 subtypes of EAATs have been identified, each of which exhibits a distinct distribution and pharmacology. Our growing appreciation for the functional significance of the EAATs is closely linked to our understanding of their pharmacology and the consequent development of inhibitors and substrates with which to delineate their activity. As was the case with EAA receptors, conformationally constrained glutamate mimics have been especially valuable in this effort. The success of these compounds is based upon the concept that restricting the spatial positions that can be occupied by required functional groups can serve to enhance both the potency and selectivity of the analogues. In the instance of the transporters, useful pharmacological probes have emerged through the introduction of additional functional groups (e.g., methyl, hydroxyl, benzyloxy) onto the acyclic backbone of glutamate and aspartate, as well as through the exploitation of novel ring systems (e.g., pyrrolidine-, cyclopropyl-, azole-, oxazole-, and oxazoline-based analogues) to conformationally lock the position of the amino and carboxyl groups. The focus of the present review is on the pharmacology of the EAATs and, in particular, the potential to identify those chemical properties that differentiate the processes of binding and translocation (i.e., substrates from non-substrate inhibitors), as well as strategies to develop glutamate analogues that act selectively among the various EAAT subtypes.

Glutamate receptor:

Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body’s most prominent neurotransmitter, the brain’s main excitatory neurotransmitter, and also the precursor for GABA, the brain’s main inhibitory neurotransmitter.[1]

Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Glutamate receptors are implicated in a number of neurological conditions. Their central role in excitotoxicity and prevalence in the central nervous system has been linked or speculated to be linked to many neurodegenerative diseases, and several other conditions have been further linked to glutamate receptor gene mutations or receptor autoantigen/antibody activity.

Transmembrane Domain

“Transmembrane Domain”

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2.

Glutamic Acid

“Glutamic acid”

Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body’s most prominent neurotransmitter, the brain’s main excitatory neurotransmitter, and also the precursor for GABA, the brain’s main inhibitory neurotransmitter.[1] Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Glutamate receptors are implicated in a number of neurological conditions. Their central role in excitotoxicity and prevalence in the central nervous system has been linked or speculated to be linked to many neurodegenerative diseases, and several other conditions have been further linked to glutamate receptor gene mutations or receptor autoantigen/antibody activity.

Glutamate receptors

Mammalian glutamate receptors are classified based on their pharmacology. However, glutamate receptors in other organisms have different pharmacology, and therefore these classifications do not hold. One of the major functions of glutamate receptors appears to be the modulation of synaptic plasticity, a property of the brain thought to be vital for memory and learning. Both metabotropic and ionotropic glutamate receptors have been shown to have an effect on synaptic plasticity.[4] An increase or decrease in the number of ionotropic glutamate receptors on a postsynaptic cell may lead to long-term potentiation or long-term depression of that cell, respectively.[5][6][7] Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating postsynaptic protein synthesis through second messenger systems.[8] Research shows that glutamate receptors are present in CNS glial cells as well as neurons.[9] These glutamate receptors are suggested to play a role in modulating gene expression in glial cells, both during the proliferation and differentiation of glial precursor cells in brain development and in mature glial cells.[10]

• General clinical implications

  • Autoimmunity and antibody interactions with glutamate receptors and their subunit genes
  • Excitotoxicity
  • Neurodegeneration

• Conditions with demonstrated associations to glutamate receptors

  • Aching
  • Attention deficit hyperactivity disorder (ADHD)
  • Autism
  • Diabetes
  • Huntington’s disease
  • Ischemia
  • Multiple sclerosis
  • Parkinson’s disease (Parkinsonism)
  • Rasmussen’s encephalitis
  • Schizophrenia
  • Seizures

• Other diseases suspected of glutamate receptor link

  • Neurodegenerative diseases with a suspected excitotoxicity link

General clinical implications

Specific medical conditions and symptoms are discussed below.

Autoimmunity and antibody interactions with glutamate receptors and their subunit genes

Various neurological disorders are accompanied by antibody or autoantigen activity associated with glutamate receptors or their subunit genes (e.g. GluR3 in Rasmussen’s encephalitis,[31] and GluR2 in nonfamilial olivopontocerebellar degeneration.[32] In 1994 GluR3 was shown to act as an autoantigen in Rasmussen’s encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33] Such findings “suggest” links between glutamate receptors and autoimmune interactions are possible and may be significant in some degenerative diseases,[32] however the exact role of such antibodies in disease manifestation is still not entirely known.[34]


Overstimulation of glutamate receptors causes neurodegeneration and neuronal damage through a process called excitotoxicity. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors (specifically NMDARs), causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.[35]

High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death.[36] Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[37] This becomes a problem for cells, as it feeds into a cycle of positive feedback cell death.

Glutamate excitotoxicity triggered by overstimulation of glutamate receptors also contributes to intracellular oxidative stress. Proximal glial cells use a cystine/glutamate antiporter (xCT) to transport cystine into the cell and glutamate out. Excessive extracellular glutamate concentrations reverse xCT, so glial cells no longer have enough cystine to synthesize glutathione (GSH), an antioxidant.[38] Lack of GSH leads to more reactive oxygen species (ROSs) that damage and kill the glial cell, which then cannot reuptake and process extracellular glutamate.[39] This is another positive feedback in glutamate excitotoxicity. In addition, increased Ca2+ concentrations activate nitric oxide synthase (NOS) and the over-synthesis of nitric oxide (NO). High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.[40]


In the case of traumatic brain injury or cerebral ischemia (e.g., cerebral infarction or hemorrhage), acute neurodegeneration caused by excitotoxicity may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure; mitochondria stop producing ATP energy. Na+/K+-ATPase can no longer maintain sodium/potassium ion concentration gradients across the plasma membrane. Glutamate transporters (EAATs), which use the Na+/K+ gradient, reverse glutamate transport (efflux) in affected neurons and astrocytes, and depolarization increases downstream synaptic release of glutamate.[41] In addition, cell death via lysis or apoptosis releases cytoplasmic glutamate outside of the ruptured cell.[42] These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.

Glutamate receptors’ significance in excitotoxicity also links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.[43]

Conditions with demonstrated associations to glutamate receptors

A number of diseases in humans have a proven association with genetic mutations of glutamate receptor genes, or autoantigen/antibody interactions with glutamate receptors or their genes. Glutamate receptors and impaired regulation (in particular, those resulting in excessive glutamate levels) are also one cause of excitotoxicity (described above), which itself has been implicated or associated with a number of specific neurodegenerative conditions where neural cell death or degradation within the brain occurs over time.[39][43]

Excessive synaptic receptor stimulation by glutamate is directly related to a many conditions. Magnesium is one of many antagonists at the glutamate receptor, and magnesium deficiencies have demonstrated relationships with many glutamate receptor-related conditions.[44]

Glutamate receptors have been found to have an influence in ischemia/stroke, seizures, Parkinson’s disease, Huntington’s disease, and aching,[45] addiction[46] and an association with both ADHD[47] and autism.[48]

In most cases these are areas of ongoing research.


Hyperalgesia is directly involved with spinal NMDA receptors. Administered NMDA antagonists in a clinical setting produce significant side effects, although more research is being done in intrathecal administration.[37] Since spinal NMDA receptors link the area of pain to the brain’s pain processing center, the thalamus, these glutamate receptors are a prime target for treatment. One proposed way to cope with the pain is subconsciously through the visualization technique.[49]

Attention deficit hyperactivity disorder (ADHD)

In 2006 the glutamate receptor subunit gene GRIN2B (responsible for key functions in memory and learning) was associated with ADHD.[50] This followed earlier studies showing a link between glutamate modulation and hyperactivity (2001),[51][51] and then between the SLC1A3 solute carrier gene-encoding part of the glutamate transporter process that mapped to a chromosome (5p12) noted in multiple ADHD genome scans.[52]

Further mutations to four different metabotropic glutamate receptor genes were identified in a study of 1013 children with ADHD compared to 4105 controls with non-ADHD, replicated in a subsequent study of 2500 more patients. Deletions and duplications affected GRM1, GRM5, GRM7 and GRM8. The study concluded that “CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9)”, “over 200 genes interacting with glutamate receptors [. .] were collectively affected by CNVs”, “major hubs of the (affected genes’) network include TNIK50, GNAQ51, and CALM”, and “the fact that children with ADHD are more likely to have alterations in these genes reinforces previous evidence that the GRM pathway is important in ADHD”.[47]

A SciBX article in January 2012 commented that “UPenn and MIT teams have independently converged on mGluRs as players in ADHD and autism. The findings suggest agonizing mGluRs in patients with ADHD”.[53]


The etiology of autism may include excessive glutamatergic mechanisms. In small studies, memantine has been shown to significantly improve language function and social behavior in children with autism.[54][55] Research is underway on the effects of memantine in adults with autism spectrum disorders.[56]

A link between glutamate receptors and autism was also identified via the structural protein ProSAP1 SHANK2 and potentially ProSAP2 SHANK3. The study authors concluded that the study “illustrates the significant role glutamatergic systems play in autism” and “By comparing the data on ProSAP1/Shank2−/− mutants with ProSAP2/Shank3αβ−/− mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.”[48]


Diabetes is a peculiar case because it is influenced by glutamate receptors present outside of the central nervous system, and it also influences glutamate receptors in the central nervous system.

Diabetes mellitus, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity. Defects of long-term potential in the hippocampus are due to abnormal glutamate receptors, to be specific the malfunctioning NMDA glutamate receptors during early stages of the disease.[57]

Research is being done to address the possibility of using hyperglycemia and insulin to regulate these receptors and restore cognitive functions. Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors.[27] Treating diabetes via glutamate receptor antagonists is possible, but not much research has been done. The difficulty of modifying peripheral GluR without having detrimental effects on the central nervous system, which is saturated with GluR, may be the cause of this.

Huntington’s disease

In 2004, a specific genotype of human GluR6 was discovered to have a slight influence on the age of onset of Huntington’s disease.[58]

In addition to similar mechanisms causing Parkinson’s disease with respect to NMDA or AMPA receptors, Huntington’s disease was also proposed to exhibit metabolic and mitochondrial deficiency, which exposes striatal neurons to the over activation of NMDA receptors.[37] Using folic acid has been proposed as a possible treatment for Huntington’s due to the inhibition it exhibits on homocysteine, which increases vulnerability of nerve cells to glutamate.[59] This could decrease the effect glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity.


During ischemia, the brain has been observed to have an unnaturally high concentration of extracellular glutamate.[60] This is linked to an inadequate supply of ATP, which drives the glutamate transport levels that keep the concentrations of glutamate in balance.[61] This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this overexposure, the postsynaptic terminals tend to keep glutamate around for long periods of time, which results in a difficulty in depolarization.[61] Antagonists for NMDA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia.[37]

Multiple sclerosis

Inducing experimental autoimmune encephalomyelitis in animals as a model for multiple sclerosis(MS) has targeted some glutamate receptors as a pathway for potential therapeutic applications.[62] This research has found that a group of drugs interact with the NMDA, AMPA, and kainate glutamate receptor to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. Oligodendrocytes in the CNS myelinate axons; the myelination dysfunction in MS is partly due to the excitotoxicity of those cells. By regulating the drugs which interact with those glutamate receptors, regulating glutamate binding may be possible, and thereby reduce the levels of Ca2+ influx. The experiments showed improved oligodendrocyte survival, and remyelination increased. Furthermore, CNS inflammation, apoptosis, and axonal damage were reduced.[62]

Parkinson’s disease (Parkinsonism)

Late onset neurological disorders, such as Parkinson’s disease, may be partially due to glutamate binding NMDA and AMPA glutamate receptors.[37] In vitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motor neurons, which was counteracted by some AMPA receptor antagonists such as GYKI 52466.[37] Research also suggests that the metabotropic glutamate receptor mGlu4 is directly involved in movement disorders associated with the basal ganglia through selectively modulating glutamate in the striatum.[63]

Rasmussen’s encephalitis

In 1994, GluR3 was shown to act as an autoantigen in Rasmussen’s encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33]


In schizophrenia, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor was found to be decreased in a subset of inhibitory interneurons in the cerebral cortex.[64] This is suggested by upregulation of GABA, an inhibitory neurotransmitter. In schizophrenia, the expression of the NR2A subunit of NDMA receptors in mRNA was experimentally undetectable in 49-73% in GABA neurons that usually express it. These are mainly in GABA cells expressing the calcium-buffering protein parvalbumin (PV), which exhibits fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic (chandelier cells) compartments of pyramidal neurons.[64] The study found the density of NR2A mRNA-expressing PV neurons was decreased by as much as 50% in subjects with schizophrenia. In addition, density of immunohistochemically labeled glutamatergic terminals with an antibody against the vesicular glutamate transporter vGluT1 also exhibited a reduction that paralleled the reduction in the NR2A-expressing PV neurons. Together, these observations suggest glutamatergic innervation of PV-containing inhibitory neurons appears to be deficient in schizophrenia.[64] Expression of NR2A mRNA has also been found to be altered in the inhibitory neurons that contain another calcium buffer, calbindin, targeting the dendrites of pyramidal neurons,[65] and the expression of the mRNA for the GluR5 kainate receptor in GABA neurons has also been found to be changed in organisms with schizophrenia.[66] Current research is targeting glutamate receptor antagonists as potential treatments for schizophrenia. Memantine, a weak, nonselective NMDA receptor antagonist, was used as an add-on to clozapine therapy in a clinical trial. Refractory schizophrenia patients showed associated improvements in both negative and positive symptoms, underscoring the potential uses of GluR antagonists as antipsychotics.[67] Furthermore, administration of noncompetitive NMDA receptor antagonists have been tested on rat models. Scientists proposed that specific antagonists can act on GABAergic interneurons, enhancing cortical inhibition and preventing excessive glutamatergic transmission associated with schizophrenia. These and other atypical antipsychotic drugs can be used together to inhibit excessive excitability in pyramidal cells, decreasing the symptoms of schizophrenia.[68]


Glutamate receptors have been discovered to have a role in the onset of epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.[69] Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing, so applying an antagonist to these receptors helps in preventing convulsions.[70]

Other diseases suspected of glutamate receptor link

Neurodegenerative diseases with a suspected excitotoxicity link

Neurodegenerative diseases suspected to have a link mediated (at least in part) through stimulation of glutamate receptors:[35][71]

  • AIDS dementia complex
  • Alzheimer’s disease
  • Amyotrophic lateral sclerosis
  • Combined systems disease (vitamin B12 deficiency)
  • Depression/anxiety
  • Drug addiction, tolerance, and dependency
  • Glaucoma
  • Hepatic encephalopathy
  • Hydroxybutyric aminoaciduria
  • Hyperhomocysteinemia and homocysteinuria
  • Hyperprolinemia
  • Lead encephalopathy
  • Leber’s disease
  • MELAS syndrome
  • Mitochondrial abnormalities (and other inherited or acquired biochemical disorders)
  • Neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies)
  • Nonketotic hyperglycinemia
  • Olivopontocerebellar atrophy (some recessive forms)
  • Essential tremor
  • Rett syndrome
  • Sulfite oxidase deficiency
  • Wernicke’s encephalopathy



1.a b c Petroff OA (December 2002). “GABA and glutamate in the human brain”. Neuroscientist 8 (6): 562–573. doi:10.1177/1073858402238515. PMID 12467378. Cite error: Invalid <ref> tag; name “pmid12467378” defined multiple times with different content (see the help page).

2. “Glutamate Receptors – Structures and Functions”. Centre of Synaptic Plasticity. University of Bristol. 2007-01-04. Retrieved 2009-12-07.

3. Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). “GABA and GABA receptors in the central nervous system and other organs”. Int. Rev. Cytol. International Review of Cytology 213: 1–47. doi:10.1016/S0074-7696(02)13011-7. ISBN 978-0-12-364617-0. PMID 11837891.

4. Debanne D, Daoudal G, Sourdet V, Russier M (2003). “Brain plasticity and ion channels”. J. Physiol. Paris 97 (4–6): 403–14. doi:10.1016/j.jphysparis.2004.01.004. PMID 15242652.

5. Maren S, Tocco G, Standley S, Baudry M, Thompson RF (1993). “Postsynaptic factors in the expression of long-term potentiation (LTP): increased glutamate receptor binding following LTP induction in vivo”. Proceedings of the National Academy of Sciences 90 (20): 9654–8. doi:10.1073/pnas.90.20.9654. PMID 8415757.

6. Pérez-Otaño I, Ehlers MD (May 2005). “Homeostatic plasticity and NMDA receptor trafficking”. Trends Neurosci. 28 (5): 229–38. doi:10.1016/j.tins.2005.03.004. PMID 15866197.

7. Asztély F, Gustafsson B (February 1996). “Ionotropic glutamate receptors. Their possible role in the expression of hippocampal synaptic plasticity”. Mol. Neurobiol. 12 (1): 1–11. doi:10.1007/BF02740744. PMID 8732537.

8. Weiler IJ, Greenough WT (August 1993). “Metabotropic glutamate receptors trigger postsynaptic protein synthesis”. Proc. Natl. Acad. Sci. U.S.A. 90 (15): 7168–71. doi:10.1073/pnas.90.15.7168. PMC 47097. PMID 8102206.

9.a b Teichberg VI (December 1991). “Glial glutamate receptors: likely actors in brain signaling”. FASEB J. 5 (15): 3086–91. PMID 1660422.

10.a b c Steinhäuser C, Gallo V (August 1996). “News on glutamate receptors in glial cells”. Trends Neurosci. 19 (8): 339–45. doi:10.1016/0166-2236(96)10043-6. PMID 8843603.

11.a b Palmada M, Centelles J (1998). “Excitatory amino acid neurotransmission. Pathways for metabolism, storage and reuptake of glutamate in brain”. Front Biosci 3: d701–18. PMID 9665875.

12. Ohashi H, Maruyama T, Higashi-Matsumoto H, Nomoto T, Nishimura S, Takeuchi Y (2002). “A novel binding assay for metabotropic glutamate receptors using [3H] L-quisqualic acid and recombinant receptors” (PDF). Z Naturforsch [C] 57 (3–4): 348–55. PMID 12064739. (subscription required (help)).

13. Suchanek B, Seeburg PH, Sprengel R (January 1995). “Gene structure of the murine N-methyl D-aspartate receptor subunit NR2C”. J. Biol. Chem. 270 (1): 41–4. doi:10.1074/jbc.270.1.41. PMID 7814402.

14. Goto H, Watanabe K, Araragi N, Kageyama R, Tanaka K, Kuroki Y, Toyoda A, Hattori M, Sakaki Y, Fujiyama A, Fukumaki Y, Shibata H (2009). “The identification and functional implications of human-specific “fixed” amino acid substitutions in the glutamate receptor family”. BMC Evol. Biol. 9: 224. doi:10.1186/1471-2148-9-224. PMC 2753569. PMID 19737383.

15. Dingledine R, Borges K, Bowie D, Traynelis SF (March 1999). “The glutamate receptor ion channels”. Pharmacol. Rev. 51 (1): 7–61. PMID 10049997.

16. Andersson O, Stenqvist A, Attersand A, von Euler G. (December 2001). “Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B”. Genomics 78 (3): 178–84. doi:10.1006/geno.2001.6666. PMID 11735224.

17. Conn PJ, et al. (2005). “Metabotropic glutamate receptors in the basal ganglia motor circuit”. Nature Reviews Neuroscience 6 (10): 787–98. doi:10.1038/nrn1763. PMID 16276355.

18. Johnson JW, Ascher P (May 1990). “Voltage-dependent block by intracellular Mg2+ of N-methyl-D-aspartate-activated channels”. Biophys. J. 57 (5): 1085–90. Bibcode:1990BpJ….57.1085J. doi:10.1016/S0006-3495(90)82626-6. PMC 1280813. PMID 1692749.

19. Crowder JM, Croucher MJ, Bradford HF, Collins JF (June 1987). “Excitatory amino acid receptors and depolarization-induced Ca2+ influx into hippocampal slices”. J. Neurochem. 48 (6): 1917–24. doi:10.1111/j.1471-4159.1987.tb05756.x. PMID 2437250.

20. Gover TD, Moreira TH, Weinreich D (2009). “Role of calcium in regulating primary sensory neuronal excitability”. Handb Exp Pharmacol 194 (194): 563–87. doi:10.1007/978-3-540-79090-7_16. PMID 19655118.

21. Barbado M, Fablet K, Ronjat M, De Waard M (June 2009). “Gene regulation by voltage-dependent calcium channels”. Biochim. Biophys. Acta 1793 (6): 1096–104. doi:10.1016/j.bbamcr.2009.02.004. PMID 19250948.

22.a b Muto T, Tsuchiya D, Morikawa K, Jingami H (March 2007). “Structures of the extracellular regions of the group II/III metabotropic glutamate receptors”. Proc. Natl. Acad. Sci. U.S.A. 104 (10): 3759–64. doi:10.1073/pnas.0611577104. PMC 1820657. PMID 17360426.

23.a b Pin JP, Acher F (June 2002). “The metabotropic glutamate receptors: structure, activation mechanism and pharmacology”. Curr Drug Targets CNS Neurol Disord 1 (3): 297–317. doi:10.2174/1568007023339328. PMID 12769621.

24. Platt SR (2007). “The role of glutamate in central nervous system health and disease–a review”. Vet. J. 173 (2): 278–86. doi:10.1016/j.tvjl.2005.11.007. PMID 16376594.

25. Kinnamon SC, Vandenbeuch A (July 2009). “Receptors and transduction of umami taste stimuli”. Ann. N. Y. Acad. Sci. 1170: 55–9. doi:10.1111/j.1749-6632.2009.04106.x. PMID 19686108.

26. Gill SS, Pulido OM, Mueller RW, McGuire PF (July 1998). “Molecular and immunochemical characterization of the ionotropic glutamate receptors in the rat heart”. Brain Res. Bull. 46 (5): 429–34. doi:10.1016/S0361-9230(98)00012-4. PMID 9739005.

27.a b Weaver CD, Yao TL, Powers AC, Verdoorn TA (May 1996). “Differential expression of glutamate receptor subtypes in rat pancreatic islets”. J. Biol. Chem. 271 (22): 12977–84. doi:10.1074/jbc.271.22.12977. PMID 8662728.

28. Bertrand G, Gross R, Puech R, Loubatières-Mariani MM, Bockaert J (June 1993). “Glutamate stimulates glucagon secretion via an excitatory amino acid receptor of the AMPA subtype in rat pancreas”. Eur. J. Pharmacol. 237 (1): 45–50. doi:10.1016/0014-2999(93)90091-U. PMID 7689469.

29. Weaver CD, Gundersen V, Verdoorn TA (January 1998). “A high affinity glutamate/aspartate transport system in pancreatic islets of Langerhans modulates glucose-stimulated insulin secretion”. J. Biol. Chem. 273 (3): 1647–53. doi:10.1074/jbc.273.3.1647. PMID 9430708.

30. Carlton SM, Hargett GL, Coggeshall RE (September 1995). “Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin”. Neurosci. Lett. 197 (1): 25–8. doi:10.1016/0304-3940(95)11889-5. PMID 8545047.

31. Carlson NG, Gahring LC, Twyman RE, Rogers SW (April 1997). “Identification of amino acids in the glutamate receptor, GluR3, important for antibody-binding and receptor-specific activation”. J. Biol. Chem. 272 (17): 11295–301. doi:10.1074/jbc.272.17.11295. PMID 9111034.

32.a b Gahring LC, Rogers SW, Twyman RE (February 1997). “Autoantibodies to glutamate receptor subunit GluR2 in nonfamilial olivopontocerebellar degeneration”. Neurology 48 (2): 494–500. doi:10.1212/wnl.48.2.494. PMID 9040745.

33.a b Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis – 1994

34. He XP, Patel M, Whitney KD, Janumpalli S, Tenner A, McNamara JO (January 1998). “Glutamate receptor GluR3 antibodies and death of cortical cells”. Neuron 20 (1): 153–63. doi:10.1016/S0896-6273(00)80443-2. PMID 9459451.

35.a b Dubinsky JM (February 1993). “Intracellular calcium levels during the period of delayed excitotoxicity”. J. Neurosci. 13 (2): 623–31. PMID 8093901. Cite error: Invalid <ref> tag; name “dub1” defined multiple times with different content (see the help page).

36. Manev H, Favaron M, Guidotti A, Costa E (July 1989). “Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death”. Mol. Pharmacol. 36 (1): 106–12. PMID 2568579.

37.a b c d e f Meldrum B (1993). “Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders”. Brain Res. Brain Res. Rev. 18 (3): 293–314. doi:10.1016/0165-0173(93)90014-Q. PMID 8401596. Cite error: Invalid <ref> tag; name “mel1” defined multiple times with different content (see the help page).

38. Aoyama K, Watabe M, Nakaki T (November 2008). “Regulation of neuronal glutathione synthesis”. J. Pharmacol. Sci. 108 (3): 227–38. doi:10.1254/jphs.08R01CR. PMID 19008644.

39.a b Markowitz AJ, White MG, Kolson DL, Jordan-Sciutto KL (July 2007). “Cellular interplay between neurons and glia: toward a comprehensive mechanism for excitotoxic neuronal loss in neurodegeneration”. Cellscience 4 (1): 111–146. PMC 2613343. PMID 19122795.

40. Nicholls DG (December 2009). “Spare respiratory capacity, oxidative stress and excitotoxicity”. Biochem. Soc. Trans. 37 (Pt 6): 1385–8. doi:10.1042/BST0371385. PMID 19909281.

41. Hirsch JA, Gibson GE (August 1984). “Selective alteration of neurotransmitter release by low oxygen in vitro”. Neurochem. Res. 9 (8): 1039–49. doi:10.1007/BF00964800. PMID 6149480.

42. Obrenovitch TP, Richards DA (1995). “Extracellular neurotransmitter changes in cerebral ischaemia”. Cerebrovasc Brain Metab Rev 7 (1): 1–54. PMID 7742171.

43.a b Beal MF (December 1992). “Mechanisms of excitotoxicity in neurologic diseases”. FASEB J. 6 (15): 3338–44. PMID 1464368.

44. Nechifor, Mihai. “Magnesium in drug dependencies”. Magnesium Research. John Libbey Eurotext. Retrieved 13 June 2013.

45. “Glutamate Receptor Summary Report”. CureHunter. Retrieved 2009-12-07.

46. Vadasz C, Saito M, Gyetvai BM, Oros M, Szakall I, Kovacs KM, Prasad VV, Toth R. (2007). “Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking.”. Genomics. 90 (6): 690–702. doi:10.1016/j.ygeno.2007.08.006.

47.a b Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, Sleiman PM, Zhang H, Kim CE, Robison R; et al. (January 2012). “Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder”. Nat. Genet. 44 (1): 78–84. doi:10.1038/ng.1013. PMID 22138692. Lay summary – Genetic Engineering & Biotechnology News.

48.a b Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, Kuebler A, Janssen AL, Udvardi PT, Shiban E, Spilker C; et al. (June 2012). “Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2”. Nature 486 (7402): 256–60. doi:10.1038/nature11015. PMID 22699619. Lay summary – AlphaGalileo Foundation.

49. Plumb B. “Glutamate – A Pain Transmitter Your Subconscious May Be Able To Limit”. EzineArticles.com.

50. Dorval KM, Wigg KG, Crosbie J, Tannock R, Kennedy JL, Ickowicz A, Pathare T, Malone M, Schachar R, Barr CL (July 2007). “Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder”. Genes Brain Behav. 6 (5): 444–52. doi:10.1111/j.1601-183X.2006.00273.x. PMID 17010153.

51.a b Gainetdinov RR, Mohn AR, Bohn LM, Caron MG (September 2001). “Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter”. Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11047–54. doi:10.1073/pnas.191353298. PMC 58681. PMID 11572967.

52. Turic D, Langley K, Williams H, Norton N, Williams NM, Moskvina V, Van den Bree MB, Owen MJ, Thapar A, O’Donovan MC (June 2005). “A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder”. Biol. Psychiatry 57 (11): 1461–6. doi:10.1016/j.biopsych.2005.03.025. PMID 15950021.

53. Osherovich L (2012). “Fine-tuning mGluRs”. Science-Business eXchange 5 (1). doi:10.1038/scibx.2012.3.

54. Chez, MG; Burton, Q; Dowling, T; Chang, M; Khanna, P; Kramer, C (May 2007). “Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability.”. Journal of child neurology 22 (5): 574–9. doi:10.1177/0883073807302611. PMID 17690064.

55. Erickson, CA; Posey, DJ; Stigler, KA; Mullett, J; Katschke, AR; McDougle, CJ (March 2007). “A retrospective study of memantine in children and adolescents with pervasive developmental disorders.”. Psychopharmacology 191 (1): 141–7. doi:10.1007/s00213-006-0518-9. PMID 17016714.

56. “A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders”.

57. Trudeau F, Gagnon S, Massicotte G (April 2004). “Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus”. Eur. J. Pharmacol. 490 (1–3): 177–86. doi:10.1016/j.ejphar.2004.02.055. PMID 15094084.

58. Diguet E, Fernagut PO, Normand E, Centelles L, Mulle C, Tison F (April 2004). “Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington’s disease natural history”. Neurobiol. Dis. 15 (3): 667–75. doi:10.1016/j.nbd.2003.12.010. PMID 15056475.

59. Wu J, Tang T, Bezprozvanny I (October 2006). “Evaluation of clinically relevant glutamate pathway inhibitors in in vitro model of Huntington’s disease”. Neurosci. Lett. 407 (3): 219–23. doi:10.1016/j.neulet.2006.08.036. PMID 16959411. Lay summary – Innovations Report.

60. Nishizawa Y. (2001). “Glutamate release and neuronal damage in ischemia”. Life Sci. 69 (4): 369–81. doi:10.1016/S0024-3205(01)01142-0. PMID 11459428.

61.a b Ottersen OP. “Sources of Glutamate in Ischemia”. Neurodegeneration Research Group. University of Oslo. Retrieved 2009-12-07.

62.a b Bolton C., Paul C. (2006). “Glutamate receptors in neuroinflammatory demyelinating disease”. Mediators of Inflammation 2006 (2): 93684. doi:10.1155/MI/2006/93684. PMC 1592583. PMID 16883070.

63. Cuomo D, et al. (2009). “Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson’s disease treatment”. J Neurochem 109 (4): 1096–105. doi:10.1111/j.1471-4159.2009.06036.x. PMID 19519781.

64.a b c BKY Bitanihirwe, MP Lim, JF Kelley, Kaneko, TUW Woo (November 2009). “Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia”. BMC Psychiatry 9: 71. doi:10.1186/1471-244X-9-71. PMC 2784456. PMID 19917116.

65. Woo TU, Shrestha K, Lamb D, Minns MM, Benes FM (April 2008). “N-Methyl-D-Aspartate Receptor and Calbindin-Containing Neurons in the Anterior Cingulate Cortex in Schizophrenia and Bipolar Disorder”. Biol Psychiatry 64 (9): 803–809. doi:10.1016/j.biopsych.2008.04.034. PMID 18585682.

66. Woo TUW, Shrestha K, Armstrong C, Minns MM, Walsh JP, Benes FM (August 2007). “Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder”. Schizophrenia Research 96 (1–3): 46–61. doi:10.1016/j.schres.2007.06.023. PMC 2712609. PMID 17698324.

67. de Lucena D, Fernandes BS, Berk M, et al. (October 2009). “Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine”. J Clin Psychiatry 70 (10): 1416–23. doi:10.4088/JCP.08m04935gry. PMID 19906345.

68. López-Gil X, Artigas F, Adell A (November 2009). “Unraveling Monoamine Receptors Involved in the Action of Typical and Atypical Antipsychotics on Glutamatergic and Serotonergic Transmission in Prefrontal Cortex”. Curr. Pharm. Des. 16 (5): 502–15. doi:10.2174/138161210790361416. PMID 19909228.

69. Chapman AG (April 2000). “Glutamate and epilepsy”. J. Nutr. 130 (4S Suppl): 1043S–5S. PMID 10736378.

70. Moldrich RX, Chapman AG, De Sarro G, Meldrum BS (August 2003). “Glutamate metabotropic receptors as targets for drug therapy in epilepsy”. Eur. J. Pharmacol. 476 (1–2): 3–16. doi:10.1016/S0014-2999(03)02149-6. PMID 12969743.

71. Gillessen T, Budd SL, Lipton SA (2002). “Excitatory amino acid neurotoxicity”. Adv. Exp. Med. Biol. 513: 3–40. doi:10.1007/978-1-4615-0123-7_1. PMID 12575816.

Our Partners