Contributions of the NMDA receptor to plasticity in hippocampal, hippocampo-cortical, and cortical circuits

N-methyl-D-aspartate (NMDA) receptor activation is thought to play a major role in neural plasticity and memory. The experiments in this thesis exploit advances in genetic technology to further elucidate the contribution of the NMDA receptor to neural plasticity within the cerebral cortex and memory processing dependent on the hippocampus. Experiment 1 examined the effect of knocking out the NR1 subunit of the NMDA receptor in the CA1 region of the hippocampus. Wild type and knock out mice were trained on transverse patterning and concurrent discrimination, two tasks that use similar stimuli and behavioral methods but differ in their demands for flexibility in memory expression. The knockouts were deficient in learning the transverse patterning task, but the deficit was overcome through the adoption of an alternate strategy. Both groups performed well on concurrent discrimination. Experiment 2 focused on the role of NMDA receptors in the hippocampus and entorhinal cortex in memory consolidation. Using AAV-Cre inducible knockout mice, NR1 was knocked out in either the hippocampus or the entorhinal cortex. Subsequently, contextual fear conditioning was assessed at short and long time points. Knocking out NR1 in the hippocampus caused disruptions in short but not long term retention of contextual fear, whereas knocking out NR1 in entorhinal cortex caused impairments at both time points. Experiment 3 focused on the role of NMDA receptors in neural plasticity within the neocortex by using the AAV-Cre inducible knockout mice. Cortical NR1 was knocked out unilaterally and the capacity for development and maintenance of long-term potentiation (LTP) was evaluated in both hemispheres using stimulation of the corpus callosum on the midline. Cortex in the AAV-Cre injected hemisphere showed no induction of LTP, whereas the saline injected hemisphere showed significant LTP. The combination of findings in these experiments supports the view that the NMDA receptor is important for synaptic plasticity in the hippocampus and cortex, and that this type of plasticity is critical to the consolidation of hippocampal dependent memory.