Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14) Increases the Excitability of Mature Hippocampal and Cortical Pyramidal Neurons

Ransdell, J. L.; Carrasquillo, Y.; Bosch, M. K.; Mellor, R. L.; Ornitz, D. M.; Nerbonne, J. M.

doi:10.1101/2024.05.04.592532

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bioRxiv · 10.1101/2024.05.04.592532

Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14) Increases the Excitability of Mature Hippocampal and Cortical Pyramidal Neurons

Ransdell, J. L.·Carrasquillo, Y.·Bosch, M. K.·Mellor, R. L.·Ornitz, D. M.·Nerbonne, J. M.

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Abstract

Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with progressive deficits in motor coordination and cognitive function. Mice (Fgf14-/-) lacking iFGF14 display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to the loss of iFGF14-mediated regulation of the voltage-dependence of inactivation of the fast transient component of the voltage-gated Na+ (Nav) current, INaT. Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal and cortical pyramidal neurons. Current-clamp recordings from adult mouse hippocampal CA1 pyramidal neurons in acute in vitro slices, however, revealed that repetitive firing rates were higher in Fgf14-/-, than in wild type (WT), cells. In addition, the waveforms of individual action potentials were altered in Fgf14-/- hippocampal CA1 pyramidal neurons, and the loss of iFGF14 reduced the time delay between the initiation of axonal and somal action potentials. Voltage-clamp recordings revealed that the loss of iFGF14 altered the voltage-dependence of activation, but not inactivation, of INaT in CA1 pyramidal neurons. Similar effects of the loss of iFGF14 on firing properties were evident in current-clamp recordings from layer 5 visual cortical pyramidal neurons. Additional experiments demonstrated that the loss of iFGF14 does not alter the distribution of anti-Nav1.6 or anti-ankyrin G immunofluorescence labeling intensity along the axon initial segments (AIS) of mature hippocampal CA1 or layer 5 visual cortical pyramidal neurons in situ. Taken together, the results demonstrate that, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, the loss of iFGF14 does not disrupt AIS architecture or Nav1.6 localization/distribution along the AIS of mature hippocampal (or cortical) pyramidal neurons in situ.

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Ransdell, J. L., Carrasquillo, Y., Bosch, M. K., Mellor, R. L., Ornitz, D. M., Nerbonne, J. M.. 2024-05-05. Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14) Increases the Excitability of Mature Hippocampal and Cortical Pyramidal Neurons. https://doi.org/10.1101/2024.05.04.592532

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