Abstract
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 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.
Highlights
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the leading identifiedReceived September 24, 2015; accepted October 28, 2015; First published November 04, 2015. 1The authors report no conflict of interest. 2Contributions: B.E.K., D.J., and D.H.B. designed the research; B.E.K. andD.H.B. performed the research; B.E.K. and D.H.B. analyzed data; B.K., D.J., and D.H.B. wrote the paper.November/December 2015, 2(6) e0114-15.2015 1–21 monogenic cause of autism
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
Testing for differences in ion channel function is complicated by heterogeneity in pyramidal neuron types within prefrontal cortex (PFC)
Summary
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the leading identifiedReceived September 24, 2015; accepted October 28, 2015; First published November 04, 2015. 1The authors report no conflict of interest. 2Contributions: B.E.K., D.J., and D.H.B. designed the research; B.E.K. andD.H.B. performed the research; B.E.K. and D.H.B. analyzed data; B.K., D.J., and D.H.B. wrote the paper.November/December 2015, 2(6) e0114-15.2015 1–21 monogenic cause of autism. Received September 24, 2015; accepted October 28, 2015; First published November 04, 2015. D.H.B. performed the research; B.E.K. and D.H.B. analyzed data; B.K., D.J., and D.H.B. wrote the paper. November/December 2015, 2(6) e0114-15.2015 1–21 monogenic cause of autism. Fragile X mental retardation protein (FMRP), the protein absent in FXS, regulates neuron function via multiple mechanisms, including protein– protein interactions, translational control, and protein trafficking (Hagerman et al, 2005; Bhakar et al, 2012; Santoro et al, 2012; Brager and Johnston, 2014). There is evidence for brain regionspecific alterations to channel function in FXS, (for review, see Contractor et al, 2015), it is unclear whether these effects are uniform across neuron types within a brain region. We provide evidence for neuron-typespecific alterations to ion channel function within the prefrontal cortex (PFC) of fmr1-/y mouse
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