Abstract
The alteration of excitatory–inhibitory (E–I) balance has been implicated in various neurological and psychiatric diseases, including autism spectrum disorder (ASD). Fragile X syndrome (FXS) is a single-gene disorder that is the most common known cause of ASD. Understanding the molecular and physiological features of FXS is thought to enhance our knowledge of the pathophysiology of ASD. Accumulated evidence implicates deficits in the inhibitory circuits in FXS that tips E–I balance toward excitation. Deficits in interneurons, the main source of an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have been reported in FXS, including a reduced number of cells, reduction in intrinsic cellular excitability, or weaker synaptic connectivity. Manipulating the interneuron activity ameliorated the symptoms in the FXS mouse model, which makes it reasonable to conceptualize FXS as an interneuronopathy. While it is still poorly understood how the developmental profiles of the inhibitory circuit go awry in FXS, recent works have uncovered several developmental alterations in the functional properties of interneurons. Correcting disrupted E–I balance by potentiating the inhibitory circuit by targeting interneurons may have a therapeutic potential in FXS. I will review the recent evidence about the inhibitory alterations and interneuron dysfunction in ASD and FXS and will discuss the future directions of this field.
Highlights
This review will discuss the pathophysiology of autism and fragile X syndrome (FXS)from a neurophysiological viewpoint
Alterations both in excitation and inhibition have been described in autism and FXS, but the inhibitory system will be the main focus in this review
PV interneurons are weaker in Fmr1 KO mice [103,104,105]. These findings indicate that PV interneurons are weaker in. These findings indicate that interneurons demonstrate immature and defective activity both intrinsically and synaptically during the immature and defective activity both intrinsically and synaptically during criticaldemonstrate period in Fmr1
Summary
This review will discuss the pathophysiology of autism and fragile X syndrome (FXS). from a neurophysiological viewpoint. Balanced excitation and inhibition in the brain is critical to maintaining proper neuronal function Alterations both in excitation and inhibition have been described in autism and FXS, but the inhibitory system will be the main focus in this review. In 2003, Rubenstein and Merzenich published a seminal review in which they proposed a model in which E–I balance was shifted towards excitation that was the basis for the pathological brain circuitry function in autism [7] Alterations both in the excitatory and inhibitory systems can result in E–I imbalance. Multiple factors, including the number of neurons, intrinsic excitability of neurons, synaptic connectivity, and network activity, can all be critical components regulating E–I balance [3] Both excitatory and inhibitory alterations have been reported in autism [8]. Inhibitory alterations, dysfunction of interneurons, the main source of an inhibitory neurotransmitter gamma-aminobutyric acid (GABA), will be the primary focus
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