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bioRxiv · 10.64898/2026.08.18.745439

Altered axonal initial segment development links circuit and Kv7 dysfunction in an Fmr1 knockout rat

Webster, J. F.·Pronot, M.·Cousin, M. A.
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Abstract

Fragile X syndrome (FXS) is the leading monogenetic cause of intellectual disability and autism, yet how basic hippocampal circuit properties evolve across development for this condition remains unclear. Here, we studied CA1 pyramidal neurons in male Fmr1 knockout rats at postnatal day (P)12 - 15 and 6 - 10 weeks using ex vivo electrophysiology pharmacology, imaging and biochemistry. P12 - 15 knockout neurons showed impaired sustained firing, progressive action potential broadening and enhanced activity-dependent synaptic vesicle replenishment. These defects recovered by 6 -10 weeks. These phenotypes were linked to Kv7 channel dysfunction, as Kv7 activation altered action potential dynamics and neurotransmission in WT but not Fmr1 KO neurons. Rather than directly altering Kv7 channel function, Fmr1 knockout altered axon initial segment (AIS) development such that Kv7 became functionally inert. These findings suggest that this drives early, transient Kv7-dependent CA1 dysfunction in FXS and highlight how alterations in AIS development can have profound functional impacts.

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Webster, J. F., Pronot, M., Cousin, M. A.. 2026-08-23. Altered axonal initial segment development links circuit and Kv7 dysfunction in an Fmr1 knockout rat. https://doi.org/10.64898/2026.08.18.745439

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