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eNeuro. 2019 Dec 3;6(6). pii: ENEURO.0217-19.2019. doi: 10.1523/ENEURO.0217-19.2019. Print 2019 Nov/Dec.

Impaired Reliability and Precision of Spiking in Adults But Not Juveniles in a Mouse Model of Fragile X Syndrome.

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National Centre for Biological Sciences, TIFR, Bellary Road, Bangalore 560065, India.
Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India.
Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, University of Edinburgh, EH8 9XD Edinburgh, United Kingdom.
National Centre for Biological Sciences, TIFR, Bellary Road, Bangalore 560065, India


Fragile X syndrome (FXS) is the most common source of intellectual disability and autism. Extensive studies have been performed on the network and behavioral correlates of the syndrome, but our knowledge about intrinsic conductance changes is still limited. In this study, we show a differential effect of FMRP knockout in different subsections of hippocampus using whole-cell patch clamp in mouse hippocampal slices. We observed no significant change in spike numbers in the CA1 region of hippocampus, but a significant increase in CA3, in juvenile mice. However, in adult mice we see a reduction in spike number in the CA1 with no significant difference in CA3. In addition, we see increased variability in spike numbers in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult mice (8 weeks) but not juvenile mice (4 weeks). This increased spiking variability was correlated with reduced spike number and with elevated AHP. The increased AHP arose from elevated SK currents (small conductance calcium-activated potassium channels), but other currents involved in medium AHP, such as I h and M, were not significantly different. We obtained a partial rescue of the cellular variability phenotype when we blocked SK current using the specific blocker apamin. Our observations provide a single-cell correlate of the network observations of response variability and loss of synchronization, and suggest that the elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference.


SK channels; fragile X syndrome; ion channels; neurodeveloment

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