Mechanisms Driving the Emergence of Neuronal Hyperexcitability in Fragile X Syndrome

Abstract

Hyperexcitability is a shared neurophysiological phenotype across various genetic neurodevelopmental disorders, including Fragile X syndrome (FXS). Several patient symptoms are associated with hyperexcitability, but a puzzling feature is that their onset is often delayed until their second and third year of life. It remains unclear how and why hyperexcitability emerges in neurodevelopmental disorders. FXS is caused by the loss of FMRP, an RNA-binding protein which has many critical roles including protein synthesis-dependent and independent regulation of ion channels and receptors, as well as global regulation of protein synthesis. Here, we discussed recent literature uncovering novel mechanisms that may drive the progressive onset of hyperexcitability in the FXS brain. We discussed in detail how recent publications have highlighted defects in homeostatic plasticity, providing new insight on the FXS brain and suggest pharmacotherapeutic strategies in FXS and other neurodevelopmental disorders.

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

“…The alterations in SWRs and MUA-SWR, we found in the dorsal KO hippocampus, were accompanied by an increase in the basal circuit excitability, as revealed by recordings of evoked potentials. The increased neuronal network excitability, often expressed as an increased E-I ratio, is a consistent observation in several brain regions of subjects with FXS including the hippocampus [see reviews by (Brager and Johnston, 2014;Contractor et al, 2015;Nelson and Valakh, 2015;10.3389/fncel.2023.1296235 Sohal and Rubenstein, 2019;Deng and Klyachko, 2021;Liu et al, 2021;Bülow et al, 2022)]. Several mechanisms may contribute to the increased excitability of the dorsal KO hippocampus, including dysregulation of various potassium channels such as Kv1, Kv4.2, large conductance potassium channels, A-type potassium channels, and hyperpolarization-activated cyclic nucleotide-gated channels (Gross et al, 2011;Brager et al, 2012;Routh et al, 2013;Zhang et al, 2014;Kalmbach et al, 2015;Brandalise et al, 2020;Kalmbach and Brager, 2020).…”

“…It is widely accepted that FXS and other neurodevelopmental disorders are mechanistically linked to a disturbance in the balance between excitation and inhibition (E-I) toward excitation in several brain regions of individuals and animal models of FXS (Nelson and Valakh, 2015;Sohal and Rubenstein, 2019). Increase of E-I ratio in FXS may result from an increased intrinsic cellular excitability and/or a reduction in synaptic inhibition (Contractor et al, 2015;Nelson and Valakh, 2015;Liu et al, 2021;Nomura, 2021;Bülow et al, 2022). 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).…”

The role of aberrant neural oscillations in the hippocampal-medial prefrontal cortex circuit in neurodevelopmental and neurological disorders

“…These findings implicate the potential for gene therapy to restore cellular changes (e.g. GABAergic deficits) and correct circuit imbalances (neuronal hyperexcitability) associated with learning disabilities, sensory hypersensitivities, and social deficits in FXS and other neurodevelopmental disorders (Bülow et al, 2022;Contractor et al, 2015). As of now, the efficacy of gene therapy in restoring abnormal HPC-mPFC circuitry remains unclear and clinical trials are warranted.…”

From circuits to behavior: Amygdala dysfunction in fragile X syndrome

“…At the cellular level, hyperexcitability within the BLA has been implicated in the pathophysiology of amygdala-based behaviors ( Bulow et al, 2022 ). Our own work has identified distinct developmental alterations in the hyperexcitability of PNs in the BLA including profound changes in intrinsic firing rates and low threshold spiking activity ( Svalina et al, 2021 , 2022 ).…”