TY - JOUR T1 - Cell-type specific channelopathies in the prefrontal cortex of the <em>fmr1-/y</em> mouse model of Fragile X syndrome JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0114-15.2015 SP - ENEURO.0114-15.2015 AU - Brian E Kalmbach AU - Daniel Johnston AU - Darrin H Brager Y1 - 2015/11/04 UR - http://www.eneuro.org/content/early/2015/11/04/ENEURO.0114-15.2015.abstract N2 - Fragile X syndrome (FXS) is caused by transcriptional silencing of the fmr1 gene resulting in the loss of fragile X mental retardation protein (FMRP) expression. FXS patients display several behavioral phenotypes associated with prefrontal cortex (PFC) dysfunction. Voltage-gated ion channels, some of which are regulated by FMRP, heavily influence PFC neuron function. Although there is evidence for brain region-specific alterations to the function a single type of ion channel in FXS, it is unclear whether subtypes of principal neurons within a brain region are affected uniformly. We tested for alterations to ion channels critical in regulating neural excitability in two subtypes of prefrontal L5 pyramidal neurons. Using somatic and dendritic patch clamp recordings, we provide evidence that the functional expression of h-channels (Ih) is down-regulated, whereas A-type K+ channel function is up-regulated in pyramidal tract-projecting (PT) neurons in the fmr1-/y mouse PFC. This is the opposite pattern of results from published findings from hippocampus where Ih is up-regulated and A-type K+ channel function is down-regulated. Additionally, we find that somatic Kv1-mediated current is down-regulated, resulting in increased excitability of fmr1-/y PT neurons. Importantly, these h- and K+ channel differences do not extend to neighboring intratelencephalic-projecting (IT) neurons. Thus, the absence of FMRP has divergent effects on the function of individual types of ion channels not only between brain regions, but also variable effects across cell types within the same brain region. Given the importance of ion channels in regulating neural circuits, these results suggest cell-type specific phenotypes for the disease.Significance Statement: Voltage-gated ion channels regulate the excitability of neurons and are altered in Fragile X syndrome (FXS), the most common form of inherited mental retardation. In the fmr1-/y mouse model of FXS, we found neuron-type specific alterations in the function of a group of ion channels within the prefrontal cortex, a brain region associated with many cognitive deficits in FXS. Because of these alterations, neurons with subcortical projections display enhanced excitability while those without subcortical projections do not. This finding highlights the need to understand FXS and tailor its treatment in a cell-type specific manner. ER -