Higher hyperpolarization activated current (Ih) in a subpopulation of hippocampal stratum oriens CA1 interneurons in Fragile X mice

Fragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the Fmr1 knockout (FX) mouse, suggest that an imbalance between excitation and inhibition in hippocampal circuits contributes to behavioral phenotypes. In addition to changes in excitatory and inhibitory synaptic transmission, changes in the intrinsic excitability of neurons can also contribute to circuit dysfunction. We and others previously identified changes in multiple voltage-gated ion channels in hippocampal excitatory pyramidal neurons in FX mice. Whether the intrinsic properties of hippocampal inhibitory interneurons are altered in FX remains largely unknown. We made whole-cell current clamp recordings from three types of interneurons in stratum oriens of the hippocampus: fast-spiking cells and two classes of low threshold spiking cells, oriens-lacunosum moleculare (OLM) and low-threshold high Ih (LTH) neurons. We found that in FX mice input resistance and action potential firing frequency were lower in LTH, but not FS or OLM, interneurons compared to wild type. LTH cell input resistance was not different between wild type and FX mice in the presence of the h-channel blocker ZD7288 suggesting a greater contribution of Ih in FX LTH cells. In agreement, we found using voltage clamp recording that Ih was higher in FX LTH cells compared to wild type. Our results suggest that the intrinsic excitability of LTH inhibitory interneurons contribute to altered excitatory/inhibitory balance in the hippocampus of FX mice. Significance statement Changes in the balance between excitation and inhibition are believed to contribute to neurodevelopmental disorders. We, and others, previously identified changes in the intrinsic properties of excitatory hippocampal neurons in a mouse model of Fragile X syndrome. In this paper we use physiological and biochemical approaches to investigate inhibitory interneurons in the CA1 region of the hippocampus of the Fragile X mouse. We found that the hyperpolarization activated current Ih is higher, which lowers the excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations contribute to the reported altered excitatory/inhibitory balance in Fragile X syndrome.