Chapter 28 The glutamate synapse in neuropsychiatric disorders: Focus on schizophrenia and Alzheimer's disease

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This chapter focuses on a recently discovered unconventional form of neurotoxicity that arises from the underexcitation of N-methyl-D-aspartate (NMDA) receptors. It is postulated that this underexcitation of NMDA receptors is operative in two major neuropsychiatric disorders—namely, schizophrenia and Alzheimer's disease. The chapter describes the type of neuronal damage produced by hypoactivation of the NMDA receptor and the complex neural circuitry that is postulated to be perturbed because of NMDA receptor hypofunction. Excessive activation of NMDA receptors plays an important role in the pathophysiology of acute central nervous system injury syndromes such as hypoxia–ischemia, trauma, and status epilepticus. Low doses of NMDA receptor antagonist drugs, such as ketamine, tiletamine, and phencyclidine, reliably injure certain cerebrocortical neurons. At these doses the injury is confined to the posterior cingulate and retrosplenial (PC/RS) cortex and consists of the formation of intracytoplasmic vacuoles in layer III–IV pyramidal neurons.

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