Schizophrenia is a severe, often chronic disorder with a lifetime prevalence of 1% in the world and thereby constitutes a significant public health concern. The symptoms of schizophrenia are classified into three broad categories: positive, negative and cognitive symptoms. Cognitive dysfunctions are regarded by some investigators as core symptoms and appear to be critical for clinical outcome. The cognitive dysfunctions in schizophrenia involve disturbances in executive function, attention, working memory, long-term memory and social learning. Cognitive impairments in schizophrenia also include dysfunctions in declarative and episodic memory, and these dysfunctions have in part been related to dysfunction of hippocampus. Indeed, many of the more recent functional imaging studies of episodic memory have provided relatively consistent evidence for abnormal hippocampal activation in patients with schizophrenia. A number of other findings provide evidence that schizophrenic patients have deficits in hippocampal volume and shape, and the evidence for hippocampal abnormalities in this disease extends to cellular levels as well.
One of the major problems in the treatment of schizophrenia is that classical and novel atypical APDs fail to improve cognitive dysfunctions in patients. In contrast, clozapine, an old APD with multiple receptor affinities involving several neurotransmittor systems, has been shown to improve some aspects of cognition in schizophrenia. This has led to an increased focus on understanding the nature of cognitive deficits in schizophrenia and the mechanisms which underlie the effects of the APDs, such as clozapine. This information is critical for research effort which tries to identify the mechanisms underlying cognitive dysfunctions and the action of clozapine which may lead to the development of efficient treatment strategies. This effort has provided with the significant finding that the main receptor-related actions of current APDs, i.e. dopamine D2 receptor and serotonin 5-HT2A receptor blockade, are not sufficient to ameliorate cognitive dysfunctions in animal models as well as in patients with schizophrenia. In fact, it seems plausible that clozapine may improve cognition via actions which involve modulation of some the main neurotransmitters systems (glutamate, GABA, and acetylcholine) implicated in cognitive functions. Consistent with cognitive dysfunction related to the prefrontal cortex, many of the cellular and molecular hippocampal abnormalities found in individuals with schizophrenia have been associated with disturbances in glutamatergic functions, with a particular focus on NMDA receptor hypofunction. One theory of the neurodevelopmental course of schizophrenia suggests that many of the cognitive and clinical symptoms of schizophrenia reflect hypofunction of NMDA receptors that manifests at or following puberty. Indeed, NMDA receptors are extremely dense in the hippocampus, and NMDA receptor antagonists disrupt hippocampal long-term potentiation, a mechanism which is suggested to underlie the encoding phase of memory. In humans, NMDA receptor antagonists, such as phencyclidine and ketamine, impair episodic memory and elicit psychomimetic symptoms including hallucinations, delusions, disorganized speech, and thought disturbances. Investigating the role of the NMDA receptor in the pathophysiology of schizophrenia is an extremely active area of schizophrenia research that may have important implications for understanding the development of cognitive deficits in patients with schizophrenia. Changes in the NMDA receptor-mediated synaptic plasticity can be influenced by a number of synaptic inputs, the phosporylated states of the receptor as well as a number of transcription factors and genetic changes implicated in neuronal plasticity.

METHOD and AIM:
Thus, the present project will focus on how APDs, especially clozapine, and combinations of clozapine with other bioactive molecules, will affect glutamate receptor-mediated glutamatergic transmission in the CA1 region of the hippocampus, using electrophysiological studies.

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