Fragile X Syndrome as an interneuronopathy: a lesson for future studies and treatments

Abstract

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability (ID) and a primary genetic cause of autism spectrum disorder (ASD). FXS arises from the silencing of the FMR1 gene causing the lack of translation of its encoded protein, the Fragile X Messenger RibonucleoProtein (FMRP), an RNA-binding protein involved in translational control and in RNA transport along dendrites. Although a large effort during the last 20 years has been made to investigate the cellular roles of FMRP, no effective and specific therapeutic intervention is available to treat FXS. Many studies revealed a role for FMRP in shaping sensory circuits during developmental critical periods to affect proper neurodevelopment. Dendritic spine stability, branching and density abnormalities are part of the developmental delay observed in various FXS brain areas. In particular, cortical neuronal networks in FXS are hyper-responsive and hyperexcitable, making these circuits highly synchronous. Overall, these data suggest that the excitatory/inhibitory (E/I) balance in FXS neuronal circuitry is altered. However, not much is known about how interneuron populations contribute to the unbalanced E/I ratio in FXS even if their abnormal functioning has an impact on the behavioral deficits of patients and animal models affected by neurodevelopmental disorders. We revise here the key literature concerning the role of interneurons in FXS not only with the purpose to better understand the pathophysiology of this disorder, but also to explore new possible therapeutic applications to treat FXS and other forms of ASD or ID. Indeed, for instance, the re-introduction of functional interneurons in the diseased brains has been proposed as a promising therapeutic approach for neurological and psychiatric disorders.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome

“…Individuals with FXS tend to exhibit increased neural responses re ected by increased ERP amplitudes to auditory stimuli compared to typically developed individuals, likely due to neural hyperexcitability (Ethridge et al, 2016;Tempio et al, 2023). The original results from the phase 2a clinical trial suggested BPN14770 reduced the ERP amplitude of the rst stimulus in a habituation pair.…”

Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

“…In autism spectrum disorders (ASD) it is assumed that a shift in the balance of excitatory and inhibitory neuronal activity (E/I-balance) represents the underlying mechanism 27,28 . Also in Fragile X syndrome, a monogenetic cognitive impairment syndrome that is the most common cause of ASD, studies hint at an altered E/I-balance 29,30 . These findings are backed up by the fact that patients often show altered glutamine and GABA levels.…”