Impaired reliability and precision of spiking in adults but not juveniles in a mouse model of Fragile X Syndrome.
Title | Impaired reliability and precision of spiking in adults but not juveniles in a mouse model of Fragile X Syndrome. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Dwivedi D, Chattarji S, Bhalla US |
Journal | eNeuro |
Date Published | 2019 Nov 04 |
ISSN | 2373-2822 |
Abstract | 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 Knock Out (KO) in different sub-sections 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 number in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult (8 weeks) but not juvenile (4 weeks) mice. 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 mAHP, such as I 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 elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference. Fragile-X syndrome leads to a range of intellectual disability effects and autism. We have found differential effect of FMRP KO in different sub sections of hippocampus where it caused an increased spiking in CA3 in juveniles and reduced spiking in CA1, in adults. We have also found that even individual neurons with this mutation exhibit increased variability in their activity patterns. Importantly, this effect emerges after six weeks of age in mice. We showed that a specific ion channel protein, SK channel, was partially responsible, and blockage of these channels led to a partial restoration of cellular activity. This is interesting as it provides a possible molecular link between activity variability in single cells, and reported irregularity in network activity. |
DOI | 10.1523/ENEURO.0217-19.2019 |
Alternate Journal | eNeuro |
PubMed ID | 31685673 |