Glutamate excitotoxicity is a significant factor in cognitive dysfunction that you may not be aware of, but really should be.
It can play a role in any number of issues, including:
In fact, glutamate excitotoxicity seems to pop up as a factor in almost every symptom of general mental malfunction, at least to some degree.
It is even related to severe neurological diseases like Parkinson’s and Alzheimer’s.
So, if you are interested in enhancing your cognition and keeping your brain healthy, it certainly helps to understand a little bit about glutamate toxicity.
What Is Glutamate?
Glutamate is the principal excitatory neurotransmitter in the brain. In fact, it is the most prevalent neurotransmitter in the human central nervous system.
Essentially, glutamate is responsible for activating various neural systems and getting them to “go.” Think of the glutamate as the gas pedal of the brain.
Neurons release glutamate, and it then binds to glutamate receptors that are located on the synapses of other neurons.
There are three classes of glutamate receptors, namely, NMDARs, AMPARs, and kainate receptors. These all play a role not just in excitatory transmission, but also in synaptic plasticity and higher cognitive functions.
Glutamate is critical to overall cognitive function, and it is involved in pretty much all nervous system activities.
The vast majority of brain neurons and synapses are involved in the glutamate system, and glutamate transmission largely mediates both cognition and emotion, two brain functions that seem to be inextricably linked.1Pessoa L. On the relationship between emotion and cognition Nat Rev Neurosci. 2008
However, abnormal levels of glutamate can induce neurotoxicity, and because of this, glutamate can be a potential contributor to several neurodegenerative disorders.2Eric H. Chang. Assessment of glutamatergic synaptic transmission and plasticity in brain slices: relevance to bioelectronic approaches Bioelectronic Medicine. 2019
The term “excitotoxicity” refers to the ability of glutamate to kill nerve cells.
Excessively activating glutamate receptors leads to excitotoxicity. It leads to the loss of post-synaptic structures, essentially killing part of the neuron through overactivation.
In other words, too much glutamate will fry your neurons.
This process can take place in acute and chronic diseases of the central nervous system.3Choi DW. Glutamate neurotoxicity and diseases of the nervous system Neuron. 1988
You become more susceptible to excitotoxicity with age. Acute excitotoxic nerve cell death can happen in response to serious injuries, such as cerebral ischemia, traumatic brain injury (TBI), hypoglycemia, and status epilepticus.4Meldrum B, et al. Excitatory amino acid neurotoxicity and neurodegenerative diseases Trends Pharmacol Sci. 1990
However, even moderately increased glutamate concentrations can induce toxicity.5Rothstein JD, et al. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity Proc Natl Acad Sci U S A. 1993
This could happen during continuous periods of stress.
A factor in glutamate excitotoxicity may be reduced ability of the brain to clear glutamate from the synapse after it is done transmitting its information.6Koolschijn PC, et al. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies Hum Brain Mapp. 2009 7Gerard Sanacora, et al. Towards a glutamate hypothesis of depression Neuropharmacology. 2012
What Are Symptoms Of High Glutamate?
The glutamate system is associated with psychiatric illness. Specifically, central nervous system glutamate dysregulation is associated with symptoms of anxiety, post-traumatic stress, obsessive-compulsive disorder (OCD), mania, depression, and psychosis.8Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders Neuropharmacology. 2012
What Causes Glutamate Excitotoxicity?
One of the significant factors contributing to glutamate excitotoxicity is stress.
In multiple trials, chronic exposure to stress in rats increased glutamate release and uptake in the hippocampus and prefrontal cortex.9Crupi R, et al. ole of Metabotropic Glutamate Receptors in Neurological Disorders Front Mol Neurosci. 2019 10Fontella FU, et al. Repeated restraint stress alters hippocampal glutamate uptake and release in the rat JNeurochem Res. 2004 11Gad M.Gilad, et al. Region-selective stress-induced increase of glutamate uptake and release in rat forebrain Brain Research, 1990
This effect was even more pronounced in older rats, indicating that glutamate toxicity becomes even more of a factor as you age.12Lowy MT, et al. Effect of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats J Neurochem. 1995
Acute episodes like ischemic stroke as well as numerous neurodegenerative diseases like amyotrophic lateral sclerosis, Alzheimer’s disease, and Huntington’s disease are all linked to excitotoxicity in humans.13Jan Lewerenz, et al. NChronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence? Front Neurosci. 2015
During brain ischemia, glutamate excitotoxicity occurs within minutes due to the rapid increase in extracellular levels.14Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view Trends Neurosci. 1999
Epilepsy can also cause increased glutamate release.15Sankar R, et al. Patterns of status epilepticus-induced neuronal injury during development and long-term consequences J Neurosci. 1998
What Foods Are High In Glutamate?
While glutamate is a neurotransmitter that your body naturally produces, the “bound” form can be found in meat, and the “free” form can be found in food additives like monosodium glutamate (MSG) as well as soy sauce and parmesan cheese.16Olney JW. Excitotoxins in foods Neurotoxicology. 1994
Glutamate And Brain Health
Moderate increases in glutamate can result in both accelerated aging and responses that protect against stress and promote recovery. So we can judge that elevated levels of glutamate do have benefits and drawbacks.17Wang X, et al. Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate BMC Genomics. 2010
Keeping proper levels of glutamate is, therefore, critical to the overall health of the brain.
Chronic excitotoxicity may be particularly relevant for age-related neurodegenerative diseases. Even a 10% increase appears to affect nerve cell structure and survival in human trials.
This could implicate glutamate excitotoxicity in many different neurodegenerative diseases.
Researchers hypothesize that glutamate excitotoxicity plays a role in motor neuron death in amyotrophic lateral sclerosis (ALS).18Carriedo SG, et al. Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro J Neurosci. 1996
In fact, the only approved drug to treat ALS acts as an inhibitor of NMDA and kainate receptors as well as rapidly clearing glutamate activity from synapses.19Azbill RD, et al. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes Brain Res. 2000
There is also evidence for chronic excitotoxicity in Alzheimer’s Disease, which may be driven by multiple factors including the sensitization of NMDA receptors, a decrease in glutamate reuptake capacity, and an increase in glutamate release.20Jan Lewerenz, et al. Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence? Front Neurosci. 2015
Beta-amyloid plaques, one of the major contributors to Alzheimer’s (and perhaps it’s most prominent sign), also appears to interfere with proper glutamate regulation.21Mattson MP, et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity J Neurosci. 1992 22Talantova M, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss Proc Natl Acad Sci U S A. 2013 23Scimemi A, et al. Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1 J Neurosci. 2013
Huntington’s Disease is a movement disorder with psychiatric and cognitive symptoms that might be related to excess glutamate.
In rats, researchers saw that NMDA receptors were hyperactive in those with Huntington’s, indicating possible glutamate dysregulation.24Zeron MM. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease Neuron. 2002
Huntington’s Disease, NMDA receptors reorganize in a way that might cause neurodegeneration. However, there is no consistent evidence that extracellular cerebral glutamate levels are much higher in HD. So, the jury is still out on glutamate’s role in this disease.
Glutamate and Depression
The vast majority of neurons and synapses in the central nervous system use glutamate as a neurotransmitter, so it may be a bit misleading to say that glutamate is ‘involved’ in mood/anxiety disorders.
Because it is so widespread, it is going to be a factor simply by default. Glutamate is a primary factor in psychiatric illness and possibly a common pathway for antidepressants.25Gerard Sanacora, et al. Towards a glutamate hypothesis of depression Neuropharmacology. 2012
The roots of a ‘glutamate hypothesis’ of depression emerged in early 1990s, when early findings showed that N-methyl-D-aspartate receptor (NMDA-R) antagonists possess antidepressant-like action.26Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions Eur J Pharmacol. 1990
Recently, ketamine has become a promising treatment for mental disorders. Ketamine is a nonselective NMDA-R antagonist mainly employed as a dissociative anesthetic and can induce rapid (within 24 hours) antidepressant effects that are sustained for at least several days after a single infusion.
Pilot clinical trials show that by antagonizing glutamate in the NMDA receptor you get antidepressant effects, supporting the notion that glutamate plays a role in these disorders.27Diazgranados N, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression Arch Gen Psychiatry. 2010 28Berman RM, et al. Antidepressant effects of ketamine in depressed patients Biol Psychiatry. 2000
Glutamatergic abnormalities can be seen in individuals afflicted with mood disorders. Multiple studies report finding elevated glutamate content and decreased glutamine/glutamate ratios in the plasma of depressed patients compared to healthy comparison subjects.29Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH. Increased serum glutamate in depressed patients Arch Psychiatr Nervenkr. 1970.30Altamura CA, et al. Plasma and platelet excitatory amino acids in psychiatric disorders Am J Psychiatry. 1993 31Mauri MC, et al. Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment JNeuropsychobiology. 1998
A large majority of studies provide evidence of reduced glutamate metabolite levels in the frontal cortex and cingulate regions of patients with major depressive disorder while they are having a depressive episode.32Auer DP, et al. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study Biol Psychiatry. 2000 33Michael N, et al. Neurotrophic effects of electroconvulsive therapy: a proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression Neuropsychopharmacology. 2003 34Michael N, et al. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression Psychol Med. 2003 35Binesh N, et al. Neurochemistry of late-life major depression: a pilot two-dimensional MR spectroscopic study J Magn Reson Imaging. 200436Glodzik-Sobanska L, et al. Single voxel proton magnetic resonance spectroscopy in post-stroke depression Psychiatry Res. 2006
A recent analysis of brain tissue also revealed elevated glutamate levels in bipolar individuals.37Lan MJ, et al. Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder Mol Psychiatry. 2009
The findings of most research consistently showed elevated glutamate in adults with this disorder.38Bhagwagar Z, et al. Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects Biol Psychiatry. 2007 39Michael N, et al. Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex Psychopharmacology (Berl). 2003 40Dager SR, et al. Brain metabolic alterations in medication-free patients with bipolar disorder Arch Gen Psychiatry. 2004
Some researchers suggest that modifying the glutamate function could be a treatment strategy for bipolar disorder.41Gerard Sanacora, et al. Targeting the Glutamatergic System to Develop Novel, Improved Therapeutics for Mood Disorders Nat Rev Drug Discov. 2009
Glutamate receptors can play a significant role in brain function and dysfunction surrounding anxiety.42Spooren W, et al. Metabotropic glutamate receptors: their therapeutic potential in anxiety Curr Top Behav Neurosci. 2010
In fact, several types of glutamate receptors may be powerful therapeutic targets in anxiety disorders, including post-traumatic stress disorder.43Raber J, et al. Novel metabotropic glutamate receptor 4 and glutamate receptor 8 therapeutics for the treatment of anxiety Expert Opin Investig Drugs. 2015
In fact, several types of glutamate receptors may be powerful therapeutic targets in anxiety disorders, including post-traumatic stress disorder.
Glutamate appears to have higher activity in the frontal cortex and hippocampal formation in persons with schizophrenia disorder. Excess glutamate may be particularly relevant to those forms of schizophrenia in which negative symptoms, cognitive deficits, and deterioration are prominent features.
Clinical studies show that drugs that enhance NMDA-receptor function reduce negative symptoms and cognitive deficits in persons with chronic schizophrenia. Glutamate transmission remains an important avenue of study for this condition.44Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia Harv Rev Psychiatry. 1996
There is now more evidence that synaptic plasticity in the hippocampus can be activated by stress. This initial period of activation is followed by a longer period where new plasticity is inhibited, probably to ensure the preservation of memory related to the stressful event.
So, once we experience the stress, it is given priority for memory preservation in the brain over new memories, and the glutamate system may be responsible for this. 45Diamond DM, et al. target=”_blank”>The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb, and traumatic memories, and the Yerkes-Dodson law Neural Plast. 2007
It is clear from rat studies that the glutaminergic system mediates fear conditioning and response.46Walker DL, Davis M. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction Pharmacol Biochem Behav. 2002
For instance, restraint stress can increase freezing behavior in rats in a contextual, fear-conditioning situation.47Conrad CD, et al. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy Behav Neurosci. 1999
However, while stress-induced decreases in neurogenesis and hippocampal plasticity may constrain memory unlearning, agents that work on the NMDA receptors have been uniquely linked to reversal learning.
This could provide a mechanism to “unlearn” the conditioned fear responses and habits that typify PTSD.48van der Meulen JA, et al. The NMDA-receptor antagonist MK-801 selectively disrupts reversal learning in rats Neuroreport. 2003
Findings from a pilot study among adults with PTSD showed that treatment targeting the glutamine pathway reduced PTSD symptoms. It also improved performance on a cognitive task assessing the ability to unlearn previously learned concepts.
This trial shows how the glutamate receptor and excitotoxicity may be involved in PTSD, fear response, and learning.49Heresco-Levy U. Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder Int J Neuropsychopharmacol. 2002
Researchers also hypothesize that glutamatergic mechanisms may have a role in certain behavioral manifestations common to PTSD, including dissociation and perceptual alterations.
This is why these symptoms show positive reactions to treatments by NMDA-agonists, such as ketamine.50Chambers RA, et al. Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation Semin Clin Neuropsychiatry. 1999
Glutamate And The Microbiome
Microflora living in the intestine could partially regulate the glutamate system.
According to current research, modulation of glutamatergic receptor activity along the microbiota-gut-brain axis may influence gut (i.e., taste, visceral sensitivity, and motility) and brain functions (stress response, mood, and behavior). Alterations in glutamatergic transmission may participate in the pathogenesis of local and brain disorders.51Andreina Baj, et al. Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis Int J Mol Sci. 2019
For example, BMAA is a glutamate-targeting, stress-inducing neurotoxin that occurs in high levels in patients with neurodegenerative diseases.
Researchers hypothesize cyanobacteria of the intestinal microbiome generate BMAA, and stress, GI tract disease, or malnutrition may raise levels and ultimately contribute to neurological dysfunction.52Schneider C. The Rush Alzheimer’s Disease Center Nurs Adm Q. 1990
The gut-brain axis is an interesting new avenue of study for cognitive scientists, with potentially significant implications for psychological and physical health.