Role of excitatory amino acid neurotransmission in synaptic plasticity and pathology. An integrative hypothesis concerning the pathogenesis and evolutionary advantages of schizophrenia-related genes.

Abstract

N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation, burst firing and the generation of patterned activity in neuronal networks; in use-dependent stabilization of synaptic connectivity in developing animals; in some forms of learning in mature animals; and in pathologies as found in brain aging. A number of these characteristics are reminiscent of several manifestations of schizophrenia and therefore we present the hypothesis that one of the genes modified in schizophrenia is directly or indirectly linked to the control of excitatory neurotransmission; possibly the normal switching on of the expression of the adult form of the NMDA receptor is delayed. Alternatively the adult form of the NMDA receptor is altered, resulting in inappropriate functioning of this receptor. The delayed or faulty expression of the adult form of the NMDA receptor, in turn, should confer a series of evolutionary advantages including protection against aging-associated brain pathologies.