Circuits driving spatial coding deficits in epilepsy

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Project Summary/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes pervasive memory impairments that significantly impact quality of life. In rodent models of TLE, my lab and others have found major deficits in learning and memory as well as in the precision and stability of CA1 place cells. However, it remains unclear whether impaired spatial coding in CA1 is primarily due to local processing deficits in hippocampus or rather is influenced by impaired spatial coding and synchronization from upstream inputs. In fact, there is significant evidence that upstream inputs into the hippocampus from the medial entorhinal cortex (MEC) may be altered in epilepsy. This proposal will test the hypothesis that both MEC inputs into the hippocampus have altered spatial coding and synchronization. To test this hypothesis, we will first use calcium imaging with miniature microscopes to characterize how chronic epilepsy alters spatial coding in MECII stellate cells and MECIII neurons, which directly input into hippocampus. Next, we will use silicon probes to record single unit firing and LFPs simultaneously in MECII, MECIII, DG, and CA1 and determine how synchronization throughout the entorhinal-hippocampal circuit is altered in epileptic mice. Finally, we will use excitatory and inhibitory DREADDs to modulate MEC neurons in control and epileptic mice and determine how each input into hippocampus alters synchronization of hippocampal circuits and spatial memory. Together, these aims will use state-of-the-art recording and manipulation techniques to determine precisely where and how spatial coding and synchronization breaks down in epileptic mice and gain new insights into the cause of cognitive deficits.