Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome

Abstract

Silence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of fragile X syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS predict impaired neural coding in the absence of FMRP. We tested the prediction by comparing hippocampus place cells in wild-type and FXS-model mice. Experience-driven CA1 synaptic function and synaptic plasticity changes are excessive in Fmr1-null mice, but CA1 place fields are normal. However, Fmr1-null discharge relationships to local field potential oscillations are abnormally weak, stereotyped, and homogeneous; also, discharge coordination within Fmr1-null place cell networks is weaker and less reliable than wild-type. Rather than disruption of single-cell neural codes, these findings point to invariant tuning of single-cell responses and inadequate discharge coordination within neural ensembles as a pathophysiological basis of cognitive inflexibility in FXS. VIDEO ABSTRACT.

Hippocampal spike‐time correlations and place field overlaps during open field foraging

“…We examined several published datasets of extracellular recordings in hippocampal areas CA1 and CA3 during open field exploratory foraging. The following datasets were included in the analysis: two CA1 sessions from a teleportation experiment reported in Jezek, Henriksen, Treves, Moser, and Moser (), five CA1 sessions recorded in the Buzsaki lab (Mizuseki et al, 2013; Mizuseki et al, ; Mizuseki, Sirota, Pastalkova, & Buzsaki, ) (specifically session ec14.215, ec14.277, ec14.333, ec14.260, and ec15.047 from the openly available hc‐3 dataset), 16 CA1 sessions from wild‐type mice, and 16 CA1 sessions from Fmr1‐null mice recorded from Sparks, Talbot, Dvorak, and Fenton (), Talbot et al (), and Dvorak, Radwan, Sparks, Talbot, and Fenton (), also taken from the openly available hc‐16 dataset, 28 CA1 sessions in three rats from a remapping experiment reported in Schlesiger et al () and Schlesiger et al () and, finally, 178 CA3 sessions from seven rats in 11 rooms reported in Alme et al (). Details about the recordings and the experimental settings can be found in the respective references.…”

“…Fmr1‐null mice are used as a model for fragile X syndrome, exhibiting symptoms of intellectual disability such as cognitive inflexibility. Talbot et al ()) report that, although these mice place fields are no different than wild‐type, the timing of CA1 spikes are somewhat less organized by the phase of theta in the knockout mice than the wild type and also the phase‐frequency discharge probabilities of the place cells appear to be less coordinated in the knockout mice than the wild type. This led us to ask whether the phase‐distance relationship is disrupted in Fmr1‐null mice.…”

“…The analysis also revealed that, in contrast to what we observed in wild‐type mice, the phase‐distance relationship was largely absent for Fmr1‐null mice. One possible reason could be that individual place cells seem to be less organized by the phase of theta in the knockout mice than the wild type and the phase‐frequency discharge probabilities of the place cells are also somewhat less coordinated in the knockout than the wild type (Talbot et al, ). It is interesting to compare the results that we found in Fmr1‐null mice in Figure with that of the jittering analysis we performed in one of the rat datasets in Figure d.…”

“…The distance d between two place fields was computed using the 2D Kolmogorov-Smirnov probability distance directly from the distributions of spike locations (Peacock, 1983 Talbot, and Fenton (2018), also taken from the openly available hc-16 dataset, 28 CA1 sessions in three rats from a remapping experiment reported in Schlesiger et al (2015) and Schlesiger et al (2018) and, finally, 178 CA3 sessions from seven rats in 11 rooms reported in Alme et al (2014). Details about the recordings and the experimental settings can be found in the respective references.…”

“…3.5 | The phase-distance relationship is impaired in Fmr1-null mice The middle row shows the results for the teleportation experiment for data pooled from two sessions in two independent environments and the bottom row shows the same relation present for mice as well (wild-type control mice, to compare with the results for knockout mice in Figure 6) Talbot et al (2018)) report that, although these mice place fields are no different than wild-type, the timing of CA1 spikes are somewhat less organized by the phase of theta in the knockout mice than the wild type and also the phase-frequency discharge probabilities of the place cells appear to be less coordinated in the knockout mice than the wild type. This led us to ask whether the phase-distance relationship is disrupted in Fmr1-null mice.…”