Glutamate Receptor Abnormalities in Schizophrenia: Implications for Innovative Treatments

Abstract

Schizophrenia is a devastating psychiatric illness that afflicts 1% of the population worldwide, resulting in substantial impact to patients, their families, and health care delivery systems. For many years, schizophrenia has been felt to be associated with dysregulated dopaminergic neurotransmission as a key feature of the pathophysiology of the illness. Although numerous studies point to dopaminergic abnormalities in schizophrenia, dopamine dysfunction cannot completely account for all of the symptoms seen in schizophrenia, and dopamine-based treatments are often inadequate and can be associated with serious side effects. More recently, converging lines of evidence have suggested that there are abnormalities of glutamate transmission in schizophrenia. Glutamatergic neurotransmission involves numerous molecules that facilitate glutamate release, receptor activation, glutamate reuptake, and other synaptic activities. Evidence for glutamatergic abnormalities in schizophrenia primarily has implicated the NMDA and AMPA subtypes of the glutamate receptor. The expression of these receptors and other molecules associated with glutamate neurotransmission has been systematically studied in the brain in schizophrenia. These studies have generally revealed region- and molecule-specific changes in glutamate receptor transcript and protein expression in this illness. Given that glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, recent drug development efforts have targeted the glutamate system. Much effort to date has focused on modulation of the NMDA receptor, although more recently other glutamate receptors and transporters have been the targets of drug development. These efforts have been promising thus far, and ongoing efforts to develop additional drugs that modulate glutamatergic neurotransmission are underway that may hold the potential for novel classes of more effective treatments for this serious psychiatric illness.

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study

“…Bustillo et al (2014) did not find age or diagnosis effects for anterior cingulate Glu but did find alterations in Gln and Gln/Glu in SZ (Bustillo et al, 2014). The reduction in Glu levels in SZ observed in this study may be potentially explained by a combination of abnormal Glu receptor function and reduced neuropil (Dickstein et al, 2007;Rubio et al, 2012). Overall, this study provides further evidence of a reduction in Glu with SZ similar to other studies (Natsubori et al, 2012(Natsubori et al, , 2003 and with age (Hadel et al, 2013).…”

Curcumin Protects against Monosodium Glutamate Neurotoxicity and Decreasing NMDA2B and mGluR5 Expression in Rat Hippocampus

“…In the present study, glutamate concentration was remarkably increased in MSG treated rats. The amino acid transporters present in neurons and glial cells are very important for the normal function of glutamatergic transmission and for the maintenance of extracellular glutamate levels below potentially excitotoxic concentrations [20]. The possible reasons for increased glutamate level in MSG treated rats is due to blockade of re-uptake of glutamate by glutamate transporter in the presynaptic neurons and decreased downstream enzymes such as glutamate decarboxylase for the inhibitory neurotransmitter gamma amino butyric acid synthesis [21].…”

Schizophrenia

“…6 This hypothesis originated from the finding that PCP and ketamine, which each block NMDA receptors, mimic both positive and negative symptoms of disease. Moreover, when given to patients with schizophrenia, ketamine also elicits positive and negative symptoms.…”