Impaired Reliability and Precision of Spiking in Adults But Not Juveniles in a Mouse Model of Fragile X Syndrome
Authors: Upinder S Bhalla
Deepanjali Dwivedi
Sumantra Chattarji
Journal: eNeuro (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: SK channels; fragile X syndrome; ion channels; neurodeveloment.
Affiliations: 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 .

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 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 Ih 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. 

Retracted: No

PubPeer comments:
 Duplicated panels with different colors in Figure 2C: ![file] , 
 The highlighted trace is a frozen noise trace riding on a current step. The same noise protocol was used for different cells. Please see the text. From the methods section: All spike variability and precision experiments were performed in current-clamp mode. A step input current stimulus of 150 pA DC for 900 ms was used for the majority of the recordings. In some cases, as indicated in the text, frozen noise and sinusoidal input currents were also used, riding on a baseline current step of 150 pA, and again for a duration of 900 ms. , 
 #1 Both WT and KO cells were subjected to the same frozen noise to assess differences if any. Thus, the same representative trace has been used for both WT and KO cells. The protocols were generated as described in the methods section All spike variability and precision experiments were performed in current-clamp mode. A step input current stimulus of 150 pA DC for 900 ms was used for the majority of the recordings. In some cases, as indicated in the text, frozen noise and sinusoidal input currents were also used, riding on a baseline current step of 150 pA, and again for a duration of 900 ms. The SDs of noise used in noise protocols were 10, 25, 50, and 100 pA with a time cutoff of u03c4 = 3 ms. For sinusoidal currents, SDs of 50 and 100 pA were used at 5 Hz. All the protocols were repeated for 25 trials. ,