Characterizing Developmental Changes in Long-Term Depression Through Chimeric NMDA Receptors

Abstract

Synaptic plasticity in the hippocampus, a key mechanism for learning and memory, involves long-term depression (LTD) mediated by NMDA receptor (NMDAR) activation. LTD, induced by low-frequency stimulation results in weaking of excitatory synaptic efficacy and shrinking of synapse size. Dysregulation in NMDAR signaling is linked to various neurological disorders, including depression, autism, schizophrenia, and Alzheimer’s disease. Although research has demonstrated that NMDARs operate through ionotropic and non-ionotropic mechanisms, the specific roles of individual NMDAR subunit functional domains in LTD induction, particularly those within GluN2A and GluN2B subunits, remain poorly understood. A developmental shift from GluN2B to GluN2A subunits at hippocampal excitatory synapses influences the ability to induce LTD, suggesting differing contributions of GluN2A and GluN2B in ionotropic or non-ionotropic signaling. This study aims to fill this gap by analyzing electrophysiological data from hippocampal slices of wild-type and transgenic mice with swapped GluN2A and GluN2B intracellular C-terminal domains, which separates ionotropic and non-ionotropic signaling. It is hypothesized that the changes in the signaling properties of GluN2A and GluN2B domains due to the switch in subunit composition will reduce the threshold for LTD induction. Field excitatory postsynaptic potentials (fEPSPs) were recorded in response to induced LTD from a 1 Hz low-frequency stimulation and assessed for input-output relationships and paired-pulse responses. Data analysis will utilize two-way ANOVA to determine the effects of age and genotype, with post-hoc tests to evaluate sex differences. This research is expected to advance understanding of the molecular mechanisms underlying LTD and inform the development of targeted therapies for cognitive and neurodegenerative disorders.