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.
Fragile X Mental Retardation Protein Bidirectionally Controls Dendritic Ih in a Cell Type-Specific Manner between Mouse Hippocampus and Prefrontal Cortex / F. Brandalise, B.E. Kalmbach, P. Mehta, O. Thornton, D. Johnston, B.V. Zemelman, D.H. Brager. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - 40:27(2020), pp. 5327-5340. [10.1523/JNEUROSCI.1670-19.2020]
|Titolo:||Fragile X Mental Retardation Protein Bidirectionally Controls Dendritic Ih in a Cell Type-Specific Manner between Mouse Hippocampus and Prefrontal Cortex|
|Parole Chiave:||CA1; Dendrite; FMRP; HCN; I; h; PFC; Animals; CA1 Region, Hippocampal; Dendrites; Electrophysiological Phenomena; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neural Conduction; Patch-Clamp Techniques; Peptide Fragments; Prefrontal Cortex; RNA, Long Noncoding|
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
|Data di pubblicazione:||2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1523/JNEUROSCI.1670-19.2020|
|Appare nelle tipologie:||01 - Articolo su periodico|