Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

Area of Science:

• Neuroscience
• Genetics
• Autism Spectrum Disorder Research

Background:

• Autism spectrum disorder (ASD) presents diverse genetic and behavioral profiles.
• Understanding convergent brain pathophysiology across genetic ASD forms is crucial.
• Atypical sensory processing is a core feature of ASD, linked to neocortical circuit function.

Purpose of the Study:

• To analyze convergent deficits in neural circuit function across multiple transgenic mouse models of ASD.
• To evaluate proposed circuit-level theories for ASD, including excitation-inhibition (E-I) ratio and parvalbumin (PV) interneuron function.
• To identify commonalities and differences in neural circuit pathophysiology underlying ASD behaviors.

Main Methods:

• Systematic review and analysis of evidence from transgenic mouse models of ASD.
• Focus on sensory areas of the neocortex and their circuit function.
• Assessment of behavioral and neurophysiological data related to sensory processing and neural coding.

Main Results:

• Heightened innate sensory detection and impaired sensory discrimination observed across many ASD models.
• Prevalence of parvalbumin (PV) interneuron hypofunction and increased excitation-inhibition (E-I) ratio, but rarely leading to hyperexcitability.
• Degraded sensory tuning and neural coding are common, potentially explaining impaired discrimination.
• Identification of two distinct phenotypic clusters with opposing neural circuit signatures.

Conclusions:

• Convergent deficits in neural circuit function exist across diverse ASD mouse models, particularly in sensory processing.
• Degraded neural coding, rather than widespread hyperexcitability, may underlie impaired sensory discrimination in ASD.
• Distinct physiological subtypes of ASD are suggested by the observed phenotypic clustering, offering potential for targeted therapies.