Convergent Excitability Defects in Prefrontal Corticothalamic Pyramidal Neurons Link Genes to Behavior in Mouse Models of Autism

Background:  

Autism is a neuropsychiatric disorder that can be caused by diverse genetic changes that converge in deep projection layers of prefrontal cortex during mid-gestational development.  How various genetic mutations cause a common behavioral phenotype of autism is poorly understood. 

Objectives:  

Our work aims to understand the neuronal circuit mechanisms in prefrontal cortex that link distinct genetic changes and environmental exposures to autism-associated behaviors.

Methods:  

We study three mouse models of autism (CNTNAP2 knockout, FMR1 knockout, and prenatal valproate exposure) at the level of cells, circuits, and behavior using slice electrophysiology, optogenetics, and behavioral assays.

Results:  

First, in vivo patch clamp electrophysiology of Layer 5 medial prefrontal pyramidal neurons shows that in the autism models, there are selective defects in the intrinsic excitability of neurons projecting to the thalamus, while the Layer 5 neurons that project to the contralateral cortex are normal. These intrinsic excitability deficits in corticothalamic cells are associated with altered responses to synaptic inputs. Finally, acute optogenetic manipulation of the corticothalamic circuit in awake, behaving mice modulates social interest in valproate-exposed mice.

Conclusions:

The medial prefrontal corticothalamic circuit is disrupted by diverse genetic and environmental causes of autism. Acute manipulation of this circuit modulates social interest, implying a causal relationship between the corticothalamic hypoexcitability and the behavioral abnormalities seen in autism.