Subtype specific dysfunction of inhibitory interneurons in Fragile-X syndrome

Inhibitory interneurons are among the most diverse cell types in the brain; the hippocampus alone contains more than 28 different inhibitory interneurons. Dysfunction of interneurons contributes to numerous neurological disorders and their subsequent study has yielded insights into brain function and clinical interventions. This dissertation will focus on the function of inhibitory interneurons in wild type and a mouse model of Fragile X syndrome. Using whole cell current-clamp, we found that spike frequency adaptation (SFA) was highly heterogeneous in low threshold spiking interneurons in the CA1 stratum oriens of wildtype mice. Analysis with k-means clustering parsed the data set into two distinct clusters based on a constellation of physiological parameters and reliably sorted strong and weak SFA cells into different groups. Interneurons with strong SFA fired fewer action potentials across a range of current inputs and had lower input resistance compared to cells with weak SFA. Strong SFA cells also had higher sag and rebound in response to hyperpolarizing current injections. Voltage-clamp recordings showed that the hyperpolarization activated current I [subscript h] was significantly larger in strong SFA cells compared to weak SFA cells. We suggest that the weak SFA cells are canonical OLM neurons and strong SFA cells represent a previously uncharacterized type of hippocampal interneuron, and we refer to them as Low Threshold High Isubscript h cells. Using whole-cell current-clamp recordings from fast spiking (FS) and low-threshold spiking (LTS) in area CA1 stratum oriens interneurons from wild type and FX mice, we found that input resistance and action potential firing frequency was lower in FX LTS, but not FS, hippocampal interneurons. LTS neurons were separated into oriens lacunosum molecular (OLM) and LTH groups. Input resistance and action potential firing frequency of LTH, but not OLM neurons, was lower in FX mice compared to WT. The difference in LTH cell input resistance was absent in the presence of h-channel blocker ZD7288 suggesting a difference in I [subscript h] between WT and FX LTH cells. Voltage-clamp experiments revealed that I [subscript h] was significantly higher in FX LTH cells compared to WT. My results on inhibitory hippocampal interneurons, together with previous results from excitatory pyramidal neurons, suggest that changes to voltage-gated ion channels contribute to the altered excitatory/inhibitory balance in the hippocampus in FXS.