Developmental Consequences of N-methyl-D-aspartate Receptor Hypofunction

• Main Author: Milenkovic, Marija
• Other Authors: Ramsey, Amy J.
• Language: en_ca
• Published: 2011
• Subjects: development; schizophrenia; glutamate; NMDA receptor; 0317
• Online Access: http://hdl.handle.net/1807/31342

NMDA receptor signaling is required for proper synapse formation, maintenance, plasticity and function. Dysregulation of the NMDA receptor has been implicated in pathophysiology of schizophrenia, which has an adult onset of symptoms. NMDA receptor deficient mice were utilized to assess the developmental consequences of NMDA receptor hypofunction. Locomotor activity was elevated throughout development; however, deficits in social interaction and working memory only manifest in adulthood and did not progress with age. Age-dependent deficits in neuron synapse biology were also detected; postsynaptic spine number was normal in juveniles, decreased post-adolescence, and progressively declined in adulthood. To investigate possible molecular mechanisms underlying the observed changes in spine number, protein levels of RhoGTPases and their downstream effectors were examined. Significant changes in Rac1 and downstream effectors were detected at different developmental stages. These studies provide clarification of the temporal sequence of events and mechanisms by which NMDA receptor dysfunction affects neurodevelopment.