Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability arising from the loss of fragile X mental retardation protein (FMRP), a protein that plays a central role in neuronal function and plasticity. FXS patients show sensory hypersensitivity, hyperarousal and hippocampus-dependent learning deficits that can be recapitulated in the FMR1 KO mice. Enhanced metabotropic glutamate receptor (mGluR) signaling and muscarinic acetylcholine receptor (mAChR) signaling in the FMR1 KO mouse are implicated as the primary causes of the disease pathogenesis. Furthermore, glutamatergic kainate receptor (KAR) function is reduced in the cortex of the FMR1 KO mice. Of note, activation of these signaling pathways leads to slow gamma-range oscillations in the hippocampus in vitro and abnormal gamma oscillations have been reported in FMR1 KO mice and patients with FXS. Thus, we hypothesized that aberrant activation of these receptors leads to the observed gamma oscillopathy. We recorded gamma oscillations induced by either cholinergic agonist carbachol (CCh), mGluR1/5 agonist Dihydroxyphenylglycine (DHPG) or ionotropic glutamatergic agonist KA from the hippocampal CA3 in WT and FMR1 KO mice in vitro. We show a specific increase in the power of DHPG- and CCh-induced gamma oscillations and reduction in the synchronicity of gamma oscillations induced by KA. We further elucidate an aberrant spiking activity during CCh-induced and kainate-induced gamma oscillations which may underlie the altered gamma oscillation synchronization in the FMR1 KO mice. Last, we also noted a reduced incidence of spontaneously-occurring hippocampal sharp wave-ripple events. Our study provides further evidence for aberrant hippocampal rhythms in the FMR1 KO mice and identifies potential signaling pathways underlying gamma band oscillopathy in FXS.

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome

“…Our finding of reduced rate of occurrence of SWRs in the dorsal KO vs. WT hippocampus is in keeping with previous observations made in mouse hippocampus in vitro (Pollali et al, 2021). We also confirm the absence of genotype effect on ripple oscillation reported by Pollali and coworkers (Pollali et al, 2021). However, it is of note that the FXS-associated alterations in SWRs in that study were obtained from the ventral-to-mid hippocampus of mice instead of the rat dorsal hippocampus we report here.…”

“…Our finding of reduced rate of occurrence of SWRs in the dorsal KO vs. WT hippocampus is in keeping with previous observations made in mouse hippocampus in vitro (Pollali et al, 2021). We also confirm the absence of genotype effect on ripple oscillation reported by Pollali and coworkers (Pollali et al, 2021).…”

“…Furthermore, FXS is accompanied by changes in gamma and theta oscillations (Radwan et al, 2016;Wang et al, 2017;Arbab et al, 2018), and alterations in gamma oscillation and SWRs have been recently detected in a Cntnap2 mouse model of autism (Paterno et al, 2021). Although there are some recent data suggesting that SWRs are altered in FXS (Boone et al, 2018;Pollali et al, 2021), the relationships between SWRs and FXS are insufficiently investigated and possible underlying mechanisms of SWR alterations in FXS remain elusive.…”