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bioRxiv · 10.1101/2022.12.20.521268

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

Hewitt, L. T.·Brager, D. H.
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Abstract

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 abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. 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 (FS) 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. Bath application of the h-channel blocker ZD7288 had a larger effect on input resistance in FX LTH cells and normalized input resistance between wild type and FX LTH cells, suggesting a greater contribution of Ih in FX LTH cells. In agreement, voltage clamp recordings showed that Ih was higher in FX LTH cells compared to wild type. Our results suggest that the intrinsic excitability of LTH inhibitory interneurons may contribute to altered inhibition in the hippocampus of FX mice. Significance statementChanges in the balance between excitation and inhibition underlie many neurodevelopmental disorders. Changes in several voltage-gated ion channels, which contribute to altered intrinsic excitability, were previously identified in excitatory hippocampal neurons in the Fmr1 mouse model of Fragile X syndrome. 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 Ih 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.

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Hewitt, L. T., Brager, D. H.. 2022-12-21. Higher hyperpolarization activated current (Ih) in a subpopulation of hippocampal stratum oriens CA1 interneurons in Fragile X mice.. https://doi.org/10.1101/2022.12.20.521268

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