Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

Abstract

The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

“…Ketamine-induced changes in mental status (Lahti et al, 1995b;Krystal et al, 1994) and brain metabolism (Vollenweider et al, 1997b;Holcomb et al, 2001;Breier et al, 1997;Lahti et al, 1995a) have been hypothesized to reflect antagonism of NMDARs located on inhibitory interneurons (probably GABAergic) in the anterior thalamus. That antagonism, in turn, may cause increased glutamate-dependent excitation in downstream cortical regions like the ACC (Farber, 2003;Newcomer et al, 1999;Krystal et al, 1994Krystal et al, , 2003Konradi and Heckers, 2003). In support of this idea, preclinical studies have revealed that NMDAR antagonism results in (1) increased frontal extracellular glutamate (Moghaddam et al, 1997;Lorrain et al, 2003;Takahata and Moghaddam, 2003) and acetylcholine levels (Giovannini et al, 1994), and (2) increased spontaneous firing rate of neurons in the frontal cortex (Moghaddam and Jackson, 2003;Homayoun et al, 2004).…”

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

“…In addition, hypofunction of the ionotropic glutamate NMDA receptor 75 and its modification 76 may play an important role in the pathophysiology and treatment of negative symptoms, respectively, and lead to inhibition of GABAergic interneurons. 77 GABA plays a key role in the function of the prefrontal cortex, an area impaired in schizophrenia 78 and linked to negative symptoms and cognitive impairment, 79,80 including working memory, a core cognitive deficit in the illness. 81 Antipsychotic drugs can modify GABA and glutamate system elements, including GABA A receptor, extracellular GABA levels and expression, glutamate transporters, 82 and neuregulin-1 (which regulates the expression of NMDA and GABA A receptors), 83 as well as ionotropic and metabotropic glutamate receptors.…”

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

“…28 Given the low a priori odds that any gene will be a risk factor, the interpretation and validity of candidate gene results is critically dependent on existing information about the biology of the gene relative to the biology of the disease. Abnormal glutamatergic signaling has been a prominent 'hypothesis' about the pathophysiology of schizophrenia, 29,30 and it has been suggested that a number of the genes currently implicated in schizophrenia are related to NMDA (N-methyl-D-aspartate) signaling in the brain. [31][32][33] An equally prominent hypothesis involves gamma-aminobutyric acid (GABA) neuronal function, [34][35][36][37] but this avenue has been relatively unexplored from a genetic perspective.…”