Impaired Dendritic Expression and Plasticity of h-Channels in the fmr1−/y Mouse Model of Fragile X Syndrome

SummaryDespite extensive research into both synaptic and morphological changes, surprisingly little is known about dendritic function in fragile X syndrome (FXS). We found that the dendritic input resistance of CA1 neurons was significantly lower in fmr1−/y versus wild-type mice. Consistent with elevated dendritic Ih, voltage sag, rebound, and resonance frequency were significantly higher and temporal summation was lower in the dendrites of fmr1−/y mice. Dendritic expression of the h-channel subunit HCN1, but not HCN2, was higher in the CA1 region of fmr1−/y mice. Interestingly, whereas mGluR-mediated persistent decreases in Ih occurred in both wild-type and fmr1−/y mice, persistent increases in Ih that occurred after LTP induction in wild-type mice were absent in fmr1−/y mice. Thus, chronic upregulation of dendritic Ih in conjunction with impairment of homeostatic h-channel plasticity represents a dendritic channelopathy in this model of mental retardation and may provide a mechanism for the cognitive impairment associated with FXS.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Electrophysiological evidence of more dendritic Ih in CA1 neurons in the fmr1−/y mouse
► Higher distal dendritic expression of HCN1 in the CA1 region of fmr1−/y mice
► Plasticity of Ih after LTP induction was impaired in the fmr1−/y mouse