Mutations of the SHANK3 gene is strongly associated with autism spectrum disorder (ASD)

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Although psychiatric disorders can be linked to particular genes, the brain regions and mechanisms underlying particular disorders are not well-understood.

Mutations or deletions of the SHANK3 gene are strongly associated with autism spectrum disorder (ASD) and a related rare disorder called Phelan-McDermid syndrome.

Mice with SHANK3 mutations also display some of the traits associated with autism, including avoidance of social interactions, but the brain regions responsible for this behavior have not been identified.

A new study by neuroscientists at MIT and colleagues in China provides clues to the neural circuits underlying social deficits associated with ASD.

The paper, published in Nature Neuroscience, found that structural and functional impairments in the anterior cingulate cortex (ACC) of SHANK3 mutant mice are linked to altered social interactions.

“Neurobiological mechanisms of social deficits are very complex and involve many brain regions, even in a mouse model,” explains Guoping Feng, the James W. and Patricia T. Poitras Professor at MIT and one of the senior authors of the study.

“These findings add another piece of the puzzle to mapping the neural circuits responsible for this social deficit in ASD models.”

The Nature Neuroscience paper is the result of a collaboration between Feng, who is also an investigator at MIT’s McGovern Institute and a senior scientist in the Broad Institute’s Stanley Center for Psychiatric Research, and Wenting Wang and Shengxi Wu at the Fourth Military Medical University, Xi’an, China.

A number of brain regions have been implicated in social interactions, including the prefrontal cortex (PFC) and its projections to brain regions including the nucleus accumbens and habenula, but these studies failed to definitively link the PFC to altered social interactions seen in SHANK3 knockout mice.

In the new study, the authors instead focused on the ACC, a brain region noted for its role in social functions in humans and animal models.

The ACC is also known to play a role in fundamental cognitive processes, including cost-benefit calculation, motivation, and decision making.

Brain region linked to altered social interactions in autism model
SHANK3 (green) is expressed along with a neural marker (NeuN) in the mouse anterior cingulate cortex. Credit: Guoping Feng

In mice lacking SHANK3, the researchers found structural and functional disruptions at the synapses, or connections, between excitatory neurons in the ACC.

The researchers went on to show that the loss of SHANK3 in excitatory ACC neurons alone was enough to disrupt communication between these neurons and led to unusually reduced activity of these neurons during behavioral tasks reflecting social interaction.

Having implicated these ACC neurons in social preferences and interactions in SHANK3 knockout mice, the authors then tested whether activating these same neurons could rescue these behaviors. Using optogenetics and specfic drugs, the researchers activated the ACC neurons and found improved social behavior in the SHANK3 mutant mice.

“Next, we are planning to explore brain regions downstream of the ACC that modulate social behavior in normal mice and models of autism,” explains Wenting Wang, co-corresponding author on the study. “This will help us to better understand the neural mechanisms of social behavior, as well as social deficits in neurodevelopmental disorders.”

Previous clinical studies reported that anatomical structures in the ACC were altered and/or dysfunctional in people with ASD, an initial indication that the findings from SHANK3 mice may also hold true in these individuals.


The term “autism” as a unique disease concept was first used by Leo Kanner in 1943. He described eight boys and three girls, aged two to eight, who were unable to use language to communicate, displaying monotonous repetitions and preoccupation with objects (Kanner, 1995).

Then in 1944, Hans Asperger identified a group of children who could not integrate into their social environment and showed certain stereotypic behaviors, but did not have the speech deficiency of typical autism (Hippler and Klicpera, 2003).

In recent years, the term autism spectrum disorder (ASD) has gained general acceptance to describe a set of multifactorial neurodevelopmental disorders, grouping disorders including autistic disorder, Asperger Syndrome, pervasive developmental disorder-not otherwise specified (PDD-NOS) and child disintegrative disorder under the umbrella ASD. Although ASD has diverse behavioral manifestations with varying degrees of severity, it has a core dyad of impairments: (1) impaired social communication and social interaction, and (2) restricted and repetitive behavior, interests or activities.

There are also a number of comorbidities associated with ASD, including intellectual disability (ID), epilepsy (Tuchman et al., 2010), anxiety, attention deficits hyperactivity disorder (ADHD), sleeping disorders, and gastrointestinal disorders (Doshi-Velez et al., 2014). ASD affects 1 in 59 children in the United States, and is about 4 times more common among boys than among girls according to the estimate from CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network (Baio et al., 2018).

Large-scale surveys show the median worldwide prevalence of ASD is 1–2% (Kim et al., 2011Blumberg et al., 2013). ASD represents a lifelong condition for patients and many of them require special educational and social support, so ASD imposes a huge financial and emotional burden on society (Lavelle et al., 2014Leigh and Du, 2015). However, only limited treatment of ASD is available, in part because the causes of ASD have not yet been clearly elucidated.

Based on current studies, strong genetic components contribute to the pathogenesis of ASD, together with environmental factors in the early stage of development. Early twin studies showed that concordance of autism in monozygotic (MZ) twins (80–90%) was much higher than that in dizygotic (DZ) twins (0–10%) (Folstein and Rutter, 1977Ritvo et al., 1985Steffenburg et al., 1989Bailey et al., 1995).

However, these early studies have their limitations because of their small sample size, restricted follow-up time, and vicissitudes of diagnostic criteria. In recent years, multiple population-based cohort studies provide more reliable evidence for ASD genetic predisposition.

The relative recurrence rate for MZ twins (153.0) is much higher than that for DZ twins (8.2) (Sandin et al., 2014) and estimates of the heritability of ASD range from 54% to 95% (Gaugler et al., 2014Sandin et al., 2014Colvert et al., 2015). In addition to genetic predisposition, known environmental risk factors of ASD include advancing parental (especially paternal) reproductive age (Gardener et al., 2009Hultman et al., 2011Sandin et al., 2012), complications during pregnancy (Brown et al., 2014Estes and McAllister, 2016) and prenatal exposure to psychotropic drugs like valproic acid (VPA) (Rasalam et al., 2005Meador et al., 2013Boukhris et al., 2016).

Recent advances in gene testing techniques have allowed identification of more than 1,000 candidate genes and copy number variants (CNVs) loci associated with ASD, according to the Simmons Foundation Autism Research Initiative (SFARI) gene database1.

It is estimated that a genetic cause can be identified in up to 25% of ASD cases, chromosomal rearrangements (encompassing rare and de novo CNVs) and coding-sequence mutations making up ∼10–20% and ∼5–10% of ASD patients, respectively (Huguet et al., 2013Ziats and Rennert, 2016).

Numerous ASD candidate genes implicated in many aspects of basic cell function such as chromatin remodeling, metabolism, mRNA translation may impact neuronal processes ranging from neurogenesis to neuron migration, axon guidance, dendrite outgrowth, and synaptic formation and function (Gilbert and Man, 2017).

Synapses are highly specialized asymmetric cell-cell junctions that are fundamental units of brain communication. ASD is diagnosed at an early stage of life, usually before three years of age, a period when intense synaptogenesis is happening (Huttenlocher and Dabholkar, 1997). Multiple studies have found that mutations in genes like NRXN, NLGNSHANKTSC1/2FMR1, and MECP2 (Table ​(Table1)1) converge on common cellular pathways that converge at the synapse (Wang T. et al., 2016Stessman et al., 2017).

ASD patients are found to carry a higher global burden of rare, large CNVs which can include known ASD associated synaptic genes, such as SHANK3 and CHD10 (Guo et al., 2017).

These genes encode cell adhesion molecules, scaffolding proteins, and proteins involved in synaptic transcription, protein synthesis and degradation, which affect various aspects of synapses, including synapse formation and elimination, synaptic transmission and plasticity, suggesting that the pathogenesis of ASD, at least in part, may be attributed to synaptic dysfunction, which can lead to functional and cognitive impairments.

Some environmental risk factors of ASD can also bring about synaptic defects. For instance, the patterns of long-term potentiation (LTP) of mice that are prenatally exposed to VPA pass from an enhanced LTP phenotype in early life to an impaired LTP phenotype in adulthood (Rinaldi et al., 2007).

Synaptic impairments caused by gene mutations and environmental factors are implicated in many other neurodevelopmental diseases including epilepsy, ID, developmental delay, and attention deficit-hyperactivity disorder (ADHD). Some neuropsychiatric disorders, including schizophrenia (SCZ), bipolar disorder and obsessive-compulsive disorder (OCD) are also associated with synaptic dysfunction.

Though rare non-syndromic gene mutations only account for a small fraction of ASD cases, they provide an excellent window to better understanding the synaptic abnormalities underlying ASD. Insight has also been gained from studies of the synaptopathology of monogenic diseases such as fragile X syndrome, tuberous sclerosis complex, and Angelman syndrome that share a high comorbidity with ASD. In this article, we will review abnormalities in synaptogenesis, synaptic elimination, synaptic transmission and plasticity that are caused by mutations of a number of ASD-associated genes, to gain a better understanding of the synaptic dysfunctions underlying ASD.


More information: Baolin Guo et al. Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice, Nature Neuroscience (2019). DOI: 10.1038/s41593-019-0445-9

Journal information: Nature Neuroscience

Provided by McGovern Institute for Brain Research

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