NEUROIMMUNE MODULATION OF HIPPOCAMPAL SYNAPTIC SIGNALING, CIRCUITS, AND MEMORY RETRIEVAL

Altered brain cytokine expression is at the core of many distinct neurological conditions that affect memory function and cognition. In order to develop therapies aimed at maintaining proper memory function in patient populations with these various conditions, it is critical to gain multilevel insight into how cytokines impact brain function and memory. Our previous studies show that mild acute neuroinflammation induced by systemic lipopolysaccharide (LPS) administration impairs context discrimination memory retrieval and disrupts pattern separation-like activity in hippocampal neuronal ensembles. Furthermore, blocking microglial activation systemically during LPS challenge with minocycline: i) abrogates increases in proinflammatory cytokines, ii) restores neural circuit activity in hippocampus, and iii) rescues context discrimination memory. However, systemic LPS-induced elevation of cytokines is brain-wide and not specific to the hippocampus. Therefore, we tested whether blocking microglial activation selectively within dorsal hippocampus (DH) is sufficient to rescue hippocampal neural circuit activity and context discrimination. Rats were trained to criterion in a context discrimination conditioning (CDC) task and received infusion of saline or minocycline (2 µg) directly into DH 5 min prior to administration of saline or LPS (i.p.; 6 h before testing). Minocycline infused directly into DH in conjunction with LPS completely blocked context memory retrieval impairment in CDC. These preliminary data provide powerful evidence that local cytokine-mediated changes within DH are sufficient for the deficits in memory retrieval following peripheral immune stimulation. In order to determine how cytokines mediate alterations in neural circuit activity, and ultimately behavior, we are examining how LPS alters synaptic function and plasticity using transcriptomic and biochemical approaches. Cellular pathway analysis of RNA microarray data from whole DH indicates dysregulation of several signaling pathways critical to memory function including glutamatergic neurotransmission, calcium signaling, actin cytoskeleton regulation, and LTP. We are now analyzing synaptoneurosomal fractions of the dentate gyrus/CA3 and CA1 hippocampal subregions of candidate proteins in these pathways, including phospho-/total cofilin and phospho-/total GluR1. Together, this multilevel analysis will provide a framework for understanding how cytokines disrupt synaptic signaling and neural circuit dynamics in hippocampus necessary for context discrimination memory function.