Paradoxical Hyperexcitability in Disorders of Neurodevelopment

Abstract

Autism Spectrum Disorder (ASD), Rett syndrome (RTT) and Angelman Syndrome (AS) are neurodevelopmental disorders (NDDs) that share several clinical characteristics, including displays of repetitive movements, developmental delays, language deficits, intellectual disability, and increased susceptibility to epilepsy. While several reviews address the biological basis of non-seizure-related ASD phenotypes, here, I highlight some shared biological mechanisms that may contribute to increased seizure susceptibility. I focus on genetic studies identifying the anatomical origin of the seizure phenotype in loss-of-function, monogenic, mouse models of these NDDs, combined with insights gained from complementary studies quantifying levels of synaptic excitation and inhibition. Epilepsy is characterized by a sudden, abnormal increase in synchronous activity within neuronal networks, that is posited to arise from excess excitation, largely driven by reduced synaptic inhibition. Primarily for this reason, elevated network excitability is proposed to underlie the causal basis for the ASD, RTT, and AS phenotypes. Although, mouse models of these disorders replicate aspects of the human condition, i.e., hyperexcitability discharges or seizures on cortical electroencephalograms, measures at the synaptic level often reveal deficits in excitatory synaptic transmission, rather than too much excitation. Resolving this apparent paradox has direct implications regarding expected outcomes of manipulating GABAergic tone. In particular, in NDDs associated with seizures, cortical circuits can display reduced, rather than normal or increased levels of synaptic excitation, and therefore suggested treatments aimed at increasing inhibition could further promote hypoactivity instead of normality. In this review, I highlight shared mechanisms across animal models for ASD, RTT, and AS with reduced synaptic excitation that nevertheless promote hyperexcitability in cortical circuits.

Daily oscillation of the excitation/inhibition ratio is disrupted in two mouse models of autism

“…The exact behavioral impact of altered E/I balance in ASD remains largely unclear. A common view states that network hyperexcitability associated with reduced inhibition and altered inhibitory plasticity impairs neural processing (for recent reviews see Antoine, 2022; Chen et al, 2022; Ferguson and Gao, 2018; Liu et al, 2022), an idea well suited to account for perceptual learning deficits resulting from impairments in sensory discrimination (Goel et al, 2018). Alternatively, it has been proposed that altered excitatory and inhibitory synaptic transmission may not be a primary effect of the ASD phenotype, but rather reflect homeostatic compensations that mitigate other types of dysfunction (Antoine et al, 2019; Domanski et al, 2019; Nelson and Valakh, 2015).…”