Progressive Alterations in Synaptic Transmission and Plasticity of Area CA1 Precede the Cognitive Impairment Associated with Neonatal Administration of MK-801.

ABSTRACT

Transient hypofunction of NMDA receptors during brain maturation has been linked to cellular and behavioral alterations that mirror symptoms of schizophrenia. In line with this notion, neonatal administration of the non-competitive NMDA receptor antagonist, MK-801, mimics the negative and cognitive symptoms of schizophrenia. By combining behavioral evaluations with extracellular recordings in acute hippocampal slices, we uncovered a progressive alteration of synaptic transmission of animals neonatally treated with MK-801. During the periadolescent stage (up to postnatal day 30), before any behavioral alterations were observed, the synaptic transmission of hippocampal area CA1 exhibited progressive signs of alteration, such as the reduction in synaptic strength and impairment of short- and long-term forms of synaptic plasticity. As expected, behavioral impairments were consistently observed during the young adult stage (postnatal day 90), a period in which a steady deterioration of long-term depression and long-term potentiation was observed. Taken together, these results suggest that synaptic dysregulation precedes behavioral deterioration in a model that mimics the negative and cognitive symptoms of schizophrenia.