Elsevier

Pharmacology & Therapeutics

Volume 97, Issue 2, February 2003, Pages 153-179
Pharmacology & Therapeutics

Associate editor: T.C. Napier
Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

https://doi.org/10.1016/S0163-7258(02)00328-5Get rights and content

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.

Introduction

Schizophrenia is a severe neuropsychiatric disorder that afflicts 1% of the world population Andreasen, 1996, Bromet & Fennig, 1999, Carpenter & Buchanan, 1994. Although it is believed that multiple pathological processes can lead to schizophrenia, we have neither identified them nor linked them to the various clinical manifestations of the disorder (Carpenter & Buchanan, 1994). Unlike other neuropsychiatric disorders such as Parkinson's disease, no single anatomical abnormality is consistently observed in schizophrenia, nor are there any biochemical tests that can confirm the clinical diagnosis.

An accurate clinical diagnosis of schizophrenia is imperative for the research effort since it provides the highest likelihood to separate multiple disease-causing processes. Based on the clinical presentation, schizophrenia must be distinguished from several schizophrenia-like psychoses, including atypical, brief reactive, schizoaffective, and schizophreniform psychosis (Carpenter & Buchanan, 1994). After this first step, schizophrenia can be further subdivided into paranoid-hallucinatory, catatonic, and disorganized subtypes.

A variety of experimental approaches have been used to formulate testable hypotheses about disease mechanisms, such as neurochemistry, neuropathology, structural brain imaging, functional neuroimaging, and pharmacology Heckers, 1997, Heckers, 2001, Lewis & Lieberman, 2000. The serendipitous discovery of antipsychotic drugs has been particularly fruitful in providing insight into the pathological processes of schizophrenia.

The observation that conventional antipsychotic drugs inhibit D2 receptors Creese et al., 1976, Snyder, 1976 has provided one of the first testable hypotheses about the etiology of schizophrenia as a malfunction of the dopaminergic system. The ‘dopamine hypothesis’ (Matthysse, 1974), which initiated the search for abnormalities of the dopaminergic system, was supported by two major clinical observation: (1) schizophrenia-like symptoms occur in amphetamine abusers, due to excessive dopamine release, and (2) D2 antagonists are efficacious in the treatment of schizophrenia (Snyder, 1973). However, the hypothesis is weakened by the lack of antipsychotic properties of some potent D2 receptor antagonists such as eticlopride. Moreover, a newer group of drugs, atypical antipsychotic drugs (Andersson et al., 1998), have behavioral benefits similar to conventional antipsychotic drugs, yet have a lower affinity for the D2 receptor (Seeman et al., 1997). Thus, while the dopaminergic system may be one factor involved in schizophrenia, the search for the disease-causing mechanisms needs to include additional candidates. Because the dopaminergic system is modulating other neurotransmitter systems in the brain, the performance of these systems in schizophrenia needs to be carefully examined. The glutamatergic system, in particular, interacts closely with the dopaminergic system, both, on the neuronal-circuitry level and on the intracellular level. Inhibition of D2 receptors by conventional antipsychotic drugs affects the glutamate system (Leveque et al., 2000), and the glutamate system has been directly implicated in schizophrenia Goff & Coyle, 2001, Olney & Farber, 1995. For instance, N-methyl-d-aspartate (NMDA) receptor antagonists exacerbate psychotic symptoms in schizophrenics (Jentsch & Roth, 1999) and they produce cognitive deficits and psychotic symptoms in healthy volunteers, strikingly reminiscent of schizophrenia (Krystal et al., 1994). These observations gave rise to the ‘glutamate hypothesis of schizophrenia.’

The dopamine hypothesis of schizophrenia predicts abnormally increased activity within the dopamine neurotransmitter system as the primary deficit, while the glutamate hypothesis of schizophrenia emphasizes abnormally decreased activity within the glutamate neurotransmitter system, particularly of NMDA receptors. Since there may be multiple forms of schizophrenia, patients may have malfunctions in just one or both systems. Moreover, both systems interact in a manner that allows dopamine D2 inhibitors to modulate an abnormally low glutamate system. As will be outlined in Section 3.3, overstimulation of D2 receptors can influence NMDA receptor activity. This interdependence of the glutamate and dopamine neurotransmitter systems could reflect an abnormality of either system in the other.

This review will illustrate how the molecular aspects of glutamate receptor activity and pharmacology support the glutamate hypothesis of schizophrenia. A dysregulated glutamate system, as proposed for schizophrenia, can affect brain development in a way that is consistent with the pathology of schizophrenia. Since excellent reviews have been published on the role of glutamate in the schizophrenic brain Goff & Coyle, 2001, Olney & Farber, 1995, Sherman et al., 1991, we will focus here on the consequences of glutamate dysfunction on neuronal development and performance. In particular, we will discuss the molecular and the pharmacologic aspects of how the glutamate and dopamine systems influence each other.

Section snippets

The various roles of glutamate neurotransmission in schizophrenia

The first indication of an altered glutamate system in schizophrenia was provided by a report of significantly reduced glutamate levels in patients (Kim et al., 1980). Since then, a variety of studies have supported a primarily hypoactive glutamate system in schizophrenia Coyle, 1996, Goff & Coyle, 2001, Goff & Wine, 1997, Jentsch & Roth, 1999, Meador-Woodruff & Healy, 2000, Olney & Farber, 1995, with secondary increased glutamate release in selected brain areas (Olney et al., 1999). A

Implications for the treatment of schizophrenia

Antipsychotic drugs are used to treat primarily psychosis in schizophrenia. However, they may also have beneficial effects on the progression of the disease. Epidemiological studies suggest that early intervention in schizophrenia with antipsychotic drugs may help to reduce psychotic symptoms in subsequent episodes and to reduce relapse Lewis & Lieberman, 2000, Lieberman et al., 2001, Robinson et al., 1999.

Antipsychotic drugs are commonly grouped into ‘conventional antipsychotic drugs’ and

Conclusion

A hypoactive glutamate system can severely impede the proper formation of neural circuits during brain development. Even if connections are formed properly and in abundance during early development, the hypoactive glutamate system can cause excessive pruning and can affect the number of synapses retained during adolescence. Moreover, the failure to properly and consistently activate GABA neurons may result in neurotoxicity. Thus, a hypoactive glutamate system has a negative influence on

Acknowledgements

This work was supported by the National Alliance for Research on Schizophrenia and Depression (C.K., S.H.) and a National Institute of Drug Abuse grant DA07134 (C.K.).

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