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

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 K v 7 channel dysfunction, as K v 7 activation altered action potential dynamics and neurotransmission in WT but not Fmr1 KO neurons. Rather than directly altering K v 7 channel function, Fmr1 knockout altered axon initial segment (AIS) development such that K v 7 became functionally inert. These findings suggest that this drives early, transient K v 7-dependent CA1 dysfunction in FXS and highlight how alterations in AIS development can have profound functional impacts.