Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioral deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviors. The neurological basis and circuitry mechanisms underlying the manifestation of these abnormal behaviors are poorly understood. Shank3 (SH3 and multiple ankyrin repeat domains 3) is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of the 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs.
Objectives:
To understand the in vivo function of Shank3 at the synapse and how a disruption of Shank3 may lead to ASD-like behavior.
Methods:
We used homologous recombination in mouse ES cells to generate Shank3 mutant mice. We combined biochemical, morphological, electrophysiological and behavioral approaches to characterize the synaptic and circuitry defects in Shank3 mutant mice.
Results:
Mice genetically engineered with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Morphological analysis revealed an increase in dendrite complexity and a reduction of spine in striatal medium spiny neurons (MSNs) of Shank3 mutant mice. Furthermore, both postsynaptic scaffolding proteins and glutamate receptor subunits are reduced in the postsynaptic density of the mutant mice. Field recordings of cortico-striatal synaptic function from acute brain slices showed that field excitatory population responses were significantly reduced in Shank3B-/- mice when compared with controls. Whole cell recordings revealed that the frequency of mEPSCs was significantly reduced in Shank3B-/- MSNs, suggesting a reduction in the number of functional synapses since no defects on presynaptic function were observed. In addition, a significant reduction of peak amplitude in Shank3B-/- MSNs was also observed, indicating a reduction in the postsynaptic response from the available synapses. Together, these data demonstrate a critical role for Shank3 in postsynaptic function in cortico-striatal circuitry.
Conclusions:
Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviors in mice.