Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome

Abstract

Fragile X Syndrome (FXS) is a neurodevelopmental disorder instigated by the absence of a key translation regulating protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP in the CNS leads to abnormal synaptic development, disruption of critical periods of plasticity, and an overall deficiency in proper sensory circuit coding leading to hyperexcitable sensory networks. However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Here, we show that in vivo layer 2/3 of the primary somatosensory cortex of the Fmr1 KO mouse exhibits basal hyperexcitability and an increase in neuronal firing rate suppression during whisker activation. This aligns with our in vitro data that indicate an increase in GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired inhibitory plasticity processes. Specifically, we find that mGluR activation sensitivity is overall diminished in the Fmr1 KO mouse leading to both a decreased spontaneous inhibitory postsynaptic input to principal cells and a disrupted form of inhibitory long-term depression (I-LTD). These data suggest an adaptive mechanism that acts to homeostatically counterbalance the cortical hyperexcitability observed in FXS.

FarmApp: a new cognitive assessment method for young people with intellectual disability

“…We found that, after controlling for age and general ability, the chromatin-related group performed significantly better than the synaptic-related group on the selective attention task, but groups did not differ in spatial short-term memory or longer term recognition. These findings are in line with current models of synaptic regulatory mechanisms and genetic disorders and their effects on attentional control (29, 30). For instance, poorer performance in tasks requiring inhibitory control have been reported in Fragile X Syndrome (FXS), in children and adults, supported both in cross-sectional and longitudinal studies (15, 31-33).…”

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

“…A strong consensus points to a decline in several aspects of GABAergic inhibition in FXS, see reviews by Paluszkiewicz et al (2011), Filice et al (2020), Van der Aa and Kooy (2020), and Nomura (2021) and manipulations that enhance GABAergic inhibition can alleviate several behavioral deficits in animal models of FXS and autism (Olmos-Serrano et al, 2011;Selimbeyoglu et al, 2017;Goel et al, 2018) as well as in experimental models of elevated cortical E-I balance (Yizhar et al, 2011); see reviews by D' Hulst and Kooy (2007), Cellot and Cherubini (2014), Lozano et al (2014), and Braat and Kooy (2015). Paradoxically, however, pharmacological treatment that enhances GABAergic transmission has not yet yielded clearly positive effects in patients with FXS (Ligsay et al, 2017;Van der Aa and Kooy, 2020); furthermore, some aspects of GABAergic inhibition are enhanced, instead of reduced, in the Fmr1-KO mice (Cea-Del Rio et al, 2020;Yang et al, 2020).…”

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome

“…Previous research suggests that FMRP has a role in the development of nociceptive pain sensitization and chronic pain (23,24), and is studied as a potential target for pain treatment (25). FMR1 knockout mice that produce no FMRP show decreased neuropathic pain, protection from nociceptive sensitization (26)(27)(28) or IL-6 induced allodynia (29), and protection from pain-induced emotional sequelae such as depression (24). FMRP is hypothesized to mediate translational control over allodynia and persistent nociceptive sensitization (29).…”