Fragile X Mental Retardation Protein Bidirectionally Controls Dendritic Ih in a Cell Type-Specific Manner between Mouse Hippocampus and Prefrontal Cortex.
Channelopathies are implicated in Fragile X syndrome (FXS), yet the dysfunction of a particular ion channel varies with cell type. We previously showed that HCN channel function is elevated in CA1 dendrites of the fmr1 -/y mouse model of FXS, but reduced in L5 PFC dendrites. Using male mice, we tested whether Fragile X Mental Retardation Protein (FMRPO), the protein whose absence causes FXS, differentially modulates HCN channels in CA1 versus L5 PFC dendrites. Using a combination of viral tools, intracellular peptide, and dendritic electrophysiology, we found that FMRP regulates HCN channels via a cell-autonomous protein-protein interaction. Virally expressed FMRP restored WT HCN channel-related dendritic properties in both CA1 and L5 neurons. Rapid intracellular perfusion of the non-mRNA binding N-terminal fragment, FMRP1-298, similarly restored dendritic function. In support of a protein-protein interaction, we found that FMRP associated with HCN-TRIP8b complexes in both hippocampus and PFC. Finally, voltage-clamp recordings showed that FMRP modulated Ih by regulating the number of functional dendritic HCN channels rather than individual channel properties. Together, these represent three novel findings as to the nature of the changes in dendritic function in CA1 and PFC neurons based on the presence or absence of FMRP. Moreover, our findings provide evidence that FMRP can regulate its targets in opposite directions depending upon the cellular milieu.SIGNIFICANCE STATEMENT Changes in dendritic function, and voltage-gated ion channels in particular, are increasingly the focus of neurological disorders. We, and others, previously identified cell type-specific channelopathies in a mouse of model of Fragile X syndrome. The present study shows that replacing Fragile X Mental Retardation Protein, which is absent in Fragile X syndrome, in adult CA1 and L5 PFC neurons regulates the number of functional dendritic HCN channels in a cell type-specific manner. These results suggest that Fragile X Mental Retardation Protein regulates dendritic HCN channels via a cell-autonomous protein--protein mechanism.
['Brandalise|Federico|F|', 'Kalmbach|Brian E|BE|0000-0003-3136-8097', 'Mehta|Preeti|P|', 'Thornton|Olivia|O|', 'Johnston|Daniel|D|0000-0002-9733-1011', 'Zemelman|Boris V|BV|0000-0003-2463-4887', 'Brager|Darrin H|DH|0000-0002-3736-0515']
D000818:Animals D056547:CA1 Region, Hippocampal D003712:Dendrites D055724:Electrophysiological Phenomena D005260:Female D051860:Fragile X Mental Retardation Protein D005600:Fragile X Syndrome D006624:Hippocampus D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009431:Neural Conduction D018408:Patch-Clamp Techniques D010446:Peptide Fragments D017397:Prefrontal Cortex D062085:RNA, Long Noncoding
dendrite Ih HCN CA1 PFC FMRP