Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function

Abstract

Mutations/deletions in the SHANK3 gene are associated with autism spectrum disorders and intellectual disability. Here, we present electrophysiological and behavioral consequences in novel heterozygous and homozygous mice with a transcriptional stop cassette inserted upstream of the PDZ domain-coding exons in Shank3 (Shank3E13). Insertion of a transcriptional stop cassette prior to exon 13 leads to loss of the two higher molecular weight isoforms of Shank3. Behaviorally, both Shank3E13 heterozygous (HET) and homozygous knockout (KO) mice display increased repetitive grooming, deficits in social interaction tasks, and decreased rearing. Shank3E13 KO mice also display deficits in spatial memory in the Morris water maze task. Baseline hippocampal synaptic transmission and short-term plasticity are preserved in Shank3E13 HET and KO mice, while both HET and KO mice exhibit impaired hippocampal long-term plasticity. Additionally, Shank3E13 HET and KO mice display impaired striatal glutamatergic synaptic transmission. These results demonstrate for the first time in this novel Shank3 mutant that both homozygous and heterozygous mutation of Shank3 lead to behavioral abnormalities with face validity for autism along with widespread synaptic dysfunction.

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

“…These mice harbor the Shank3 mutation in the PDZ domain and were reported to display remarkably high levels of repetitive self-grooming and social deficits [16]. Of note, similar results were reported by Craig Powell and coworkers using a different genetic manipulation of the Shank3 gene [19]. Our larger goal for the present report and for related PACT studies is to identify behavioral phenotypes that replicate consistently in independent cohorts of mice within and between laboratories, in order to strengthen the use of preclinical mouse models of ASD, (a) for understanding the mechanistic underpinnings of ASD-relevant phenotypes, and (b) for preclinical translation in evaluating the therapeutic potential of novel treatments.…”

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

“…Disruption of Shank3B expression did not result in gross neurobiological differences in hippocampal or white matter volume, at least as measured here. Previous studies have established a decrease in NMDAR‐mediated hippocampal LTP in Shank3 KOs (Bozdagi et al, 2010; Wang et al, 2011; Yang et al, 2012; Kouser et al, 2013; Jaramillo et al, 2017). Shank3 is also involved in controlling actin dynamics and glutamate receptor‐mediated synaptic transmission and plasticity (Peça et al, 2011; Verpelli et al, 2011; Durand et al, 2012; Duffney et al, 2013; Chana et al, 2015; Sarowar and Grabrucker, 2016).…”

The Role of Interneurons in Autism and Tourette Syndrome

“…Shank3 deletions in mice produce social deficits, stereotypic behavior and aberrant cortical and striatal synaptic neurotransmission [68–70]. There is evidence that in these models the PV+ circuitry has a reduction in its perineuronal net over PC cells, resulting in a dysregulation in cortical networks due to an E/I imbalance [71].…”