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bioRxiv · 10.1101/2020.07.30.228874

Fragile X Mental Retardation Protein modulates somatic D-type K+ channels and action potential threshold in the mouse prefrontal cortex

Kalmbach, B.·Brager, D. H.
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Abstract

Axo-somatic K+ channels control action potential output in part by acting in concert with voltage-gated Na+ channels to set action potential threshold. Slowly inactivating, D-type K+ channels are enriched at the axo-somatic region of cortical pyramidal neurons of the prefrontal cortex where they regulate action potential firing. We previously demonstrated that D-type K+ channels are down regulated in extratelencephalic-projecting L5 neurons (ET) in the prefrontal cortex of the fmr1 knockout mouse model of Fragile X syndrome (FX mice), resulting in a hyperpolarized action potential threshold. To test whether K+ channel alterations are regulated in a cell autonomous manner in FXS, we used a viral-mediated approach to restore expression of Fragile X Mental Retardation Protein (FMRP) in a small population of prefrontal neurons in male FX mice. Outside-out voltage clamp recordings revealed a higher D-type K+ conductance in FMRP-positive ET neurons compared to nearby FMRP-negative ET neurons. FMRP did not affect either rapidly inactivating A-type or non-inactivating K+ conductance. ET neuron patches recorded with FMRP1-298, a truncated form of FMRP which lacks mRNA binding domains, included in the pipette solution had larger D-type K+ conductance compared to heat-inactivated controls. Viral expression of FMRP in FX mice depolarized action potential threshold to near wild type levels in ET neurons. These results suggest that FMRP influences the excitability of ET neurons in the mPFC by regulating somatic D-type K+ channels in a cell autonomous, protein-protein dependent manner.

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Kalmbach, B., Brager, D. H.. 2020-07-30. Fragile X Mental Retardation Protein modulates somatic D-type K+ channels and action potential threshold in the mouse prefrontal cortex. https://doi.org/10.1101/2020.07.30.228874

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