Proposal Summary
Neuronal circuits maintain a delicate balance of excitatory drive and inhibitory regulation to execute high order
functions, such as learning and memory, and maintain network stability which is severely compromised in
temporal lobe epilepsy (TLE). With a better understanding of mechanisms of memory formation and how TLE
disrupts the processes, we gain insights that can be used to improve memory deficits in disease. The
hippocampal dentate gyrus (DG) acts as a functional gate into the hippocampal trisynaptic circuit and plays a
key role in learning and memory. Formation of memories is believed to be coded by activity of a distinct collection
of neurons which represent a memory or experience known as an engram. Sparse activity in dentate granule
cells (GCs) has been shown to be involved in engram formation; however, the circuit mechanism that underlie
formation of these neuronal activity patterns are not fully understood. The DG is a circuit with low spontaneous
activity and robust inhibition of the projection neurons, the GCs, by local inhibitory neurons (IN). Recent studies
have found that a sparse subtype of dentate projection neurons, semilunar granule cell (SGC) are preferentially
recruited in engrams. SGCs differ from GCs in their wide dendritic arbors, molecular layer axon collaterals and
persistent firing and have been proposed to support feedback inhibition of GCs. However, circuit connectivity
and functional effects of SGCs are not known. My objective is to better understand SGC’s role in information
processing as well as their involvement in microcircuit changes related to epilepsy. I hypothesize SGCs differ
from GCs in their input integration and SGCs that outputs directly activate a subset of GCs involved memory
engrams and further refine GC engrams by engaging feedback inhibition of surrounding “non-engram” GCs. In
acquired epilepsy, I propose that SGC’s support of the DG inhibitory gate is compromised and SGC dependent
excitation increased resulting learning deficits. Aim 1 will identify differences in afferent inputs to GCs and SGCs
using virally mediated pathway specific expression of channelrhodopsin to activate distinct DG inputs and adopt
morphometric computational modeling to test the effect of dendritic structure on input integration in SGCs and
GCs. Aim 2 will use the inducible cFOS TRAP2 system coupled to fluorescent reporters to label neurons active
during a specific memory task followed by electrophysiology to determine how SGC output influences activity of
GCs within and outside the shared engram. Finally, in Aim 3, will examine how engram stability, SGC activity
and its influence on GC activity are altered in the pilocarpine model of experimental epilepsy. Together these
studies will provide novel fundamental insights into dentate circuit function and memory processing and how
these are altered in epilepsy and enable future development of circuit-based therapies to improve memory
function.
