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

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. This work was funded by a grant from the Simons Foundation to MAC (529508) and a Marie-Curie Skłodowska/UK Research and Innovation Guarantee Award to MP (EP/Y024559/1). James Hogg and Nawon Kim are both thanked for their preparation of primary neuronal cultures.

Institute for Neuroscience and Cardiovascular Research, George Square, University of Edinburgh, EH8 9XD, Edinburgh, UK Jack F. Webster, Marie Pronot & Michael A. Cousin Simons Initiative for the Developing Brain, George Square, University of Edinburgh, EH8 9XD, Edinburgh, UK Muir Maxwell Epilepsy Centre, George Square, University of Edinburgh, EH8 9XD, Edinburgh, UK Correspondence to Jack F.

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