Input-Output Relationship of CA1 Pyramidal Neurons Reveals Intact Homeostatic Mechanisms in a Mouse Model of Fragile X Syndrome

Summary Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. Here, we show increased axon initial segment length in CA1 of the Fmr1−/y mouse hippocampus, with increased cellular excitability. This change in length does not result from reduced AIS plasticity, as prolonged depolarization induces changes in AIS length independent of genotype. However, depolarization does reduce cellular excitability, the magnitude of which is greater in Fmr1−/y neurons. Finally, we observe reduced functional inputs from the entorhinal cortex, with no genotypic difference in the firing rates of CA1 pyramidal neurons. This suggests that AIS-dependent hyperexcitability in Fmr1−/y mice may result from adaptive or homeostatic regulation induced by reduced functional synaptic connectivity. Thus, while AIS length and intrinsic excitability contribute to cellular hyperexcitability, they may reflect a homeostatic mechanism for reduced synaptic input onto CA1 neurons.
Graphical Abstract
Highlights • Fmr1−/y neurons in CA1 are hyperexcitable, with longer axon initial segments • Pyramidal cells respond more strongly to prolonged depolarization in Fmr1−/y mice • Temporoammonic input to CA1 is reduced in the Fmr1−/y mouse • Cellular hyperexcitability equalizes neuron firing to reduced temporoammonic input
Neuronal hyperexcitability may underlie many features of fragile X syndrome. Booker et al. show that in hippocampal area CA1, pyramidal neurons are hyperexcitable, with longer axon initial segments. This hyperexcitability helps neurons to overcome a strong reduction in synaptic input from the entorhinal cortex, thus homeostatically regulating local network outputs.