Higher hyperpolarization-activated current in a subpopulation of interneurons in stratum oriens of area CA1 in the hippocampus of 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 <i>Fmr1</i> knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. In FX mice, changes in multiple voltage-gated ion channels occur in excitatory pyramidal neurons of the hippocampus. Whether there are also changes in the intrinsic properties of hippocampal inhibitory interneurons, however, remains largely unknown. We made whole cell current clamp recordings from both fast-spiking (FS) and low threshold spiking (LTS) interneurons in the stratum oriens region of the hippocampus. We found that LTS, but not FS, interneurons in FX mice had lower input resistance and action potential firing compared with the wild type. When we subdivided LTS interneurons into low-threshold high hyperpolarization-activated current (<i>I</i>_h) (LTH) and putative oreins-lacunosum moleculare (OLM) cells (Hewitt et al. <i>Physiol Rep</i> 9: e14848, 2021), we found that it was the LTH subgroup that had significantly lower input resistance in FX mice. The difference in input resistance between wild-type and FX LTH interneurons was absent in the presence of the h-channel blocker ZD7288, suggesting a greater contribution of <i>I</i>_h in FX LTH interneurons. Voltage clamp recordings found that indeed, <i>I</i>_h was significantly higher in FX LTH interneurons compared with wild type. Our results suggest that altered inhibition in the hippocampus of FX mice may be due in part to changes in the intrinsic excitability of LTH inhibitory interneurons.<b>NEW & NOTEWORTHY</b> In this paper, we use physiological and biochemical approaches to investigate the intrinsic excitability of inhibitory interneurons in hippocampal area CA1 of the fragile X mouse. We found that higher <i>I</i>_h lowers the intrinsic excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations may contribute to the altered excitatory/inhibitory balance in fragile X syndrome.