Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

Abstract

The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain’s principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus–pituitary–adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

“…Medications that attenuate glutamate release or block N-methyl-D-aspartate (NMDA) receptors [ 21 , 24 , 25 , 26 ] are used to treat anxiety disorders. Glutamate is the major excitatory neurotransmitter in the brain, essential for long-term potentiation and mediating long-term depression, and provides the molecular and cellular mechanisms of learning [ 27 , 28 , 29 ]. Poor long-term cognitive evaluation in patients with TBI was correlated with higher levels of brain glutamate recorded one week [ 30 ] and one month after the injury [ 31 ], confirming the link between glutamate excess and deficits in higher cognitive function.…”

“…A healthy BBB effectively prevents glutamate from moving between the intraparenchymal and blood compartments [ 36 ]. There are a number of mechanisms that cause an increase in brain glutamate associated with TBI: (i) neuronal death [ 37 ]; (ii) inflammation [ 38 , 39 , 40 , 41 , 42 ]; (iii) impaired glutamatergic recycling and signaling [ 43 ]; (iv) prolonged stress [ 29 ]; (v) astrocytic release of adenosine triphosphate (ATP) [ 44 ]; and (vi) other sources of elevated intraparenchymal glutamate [ 36 , 45 ]. Above all, however, we find the mechanisms of BBB destruction to be a significant factor in increased brain glutamate and its association with TBI [ 35 ].…”

Human genetic adaptation related to cellular zinc homeostasis

“…We could speculate that the derived G-allele, which we have shown provides better protection to the mitochondria, could help to overcome zinc overload derived from excitotoxicity, ischemia or exacerbated ROS production ( 52 ). Interestingly, dysfunctional glutamatergic signaling is associated with neuropsychiatric conditions such as schizophrenia, major depression and anxiety among others ( 51, 53, 54 ). Moreover, considering the involvement of the mitochondria in the pathogenesis of several neuropsychiatric disorders ( 55 – 57 ), the differential molecular phenotypes of the Met50Val substitution reported here may help to provide mechanistic links to these associated traits.…”

“…Interestingly, dysfunctional glutamatergic signaling is associated with neuropsychiatric conditions such as schizophrenia, major depression and anxiety among others (51,53,54).…”

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

“…In particular, the imbalance between stimulant (i.e., glutamate) and suppressor (i.e., GABA) NTs significantly affects cell excitability. Given that glutamate is the main excitatory NT in the CNS, it has been widely agreed that glutamatergic hyperexcitation can provoke seizures [ 86 , 87 , 88 , 89 ].…”