Shankopathies in the Developing Brain in Autism Spectrum Disorders

Abstract

The SHANK family of proteins play critical structural and functional roles in the postsynaptic density (PSD) at excitatory glutamatergic synapses. Through their multidomain structure they form a structural platform across the PSD for protein–protein interactions, as well as recruiting protein complexes to strengthen excitatory synaptic transmission. Mutations in SHANKs reflect their importance to synapse development and plasticity. This is evident in autism spectrum disorder (ASD), a neurodevelopmental disorder resulting in behavioural changes including repetitive behaviours, lack of sociability, sensory issues, learning, and language impairments. Human genetic studies have revealed ASD mutations commonly occur in SHANKs. Rodent models expressing these mutations display ASD behavioural impairments, and a subset of these deficits are rescued by reintroduction of Shank in adult animals, suggesting that lack of SHANK during key developmental periods can lead to permanent changes in the brain’s wiring. Here we explore the differences in synaptic function and plasticity from development onward in rodent Shank ASD models. To date the most explored brain regions, relate to the behavioural changes observed, e.g., the striatum, hippocampus, sensory, and prefrontal cortex. In addition, less-studied regions including the hypothalamus, cerebellum, and peripheral nervous system are also affected. Synaptic phenotypes include weakened but also strengthened synaptic function, with NMDA receptors commonly affected, as well as changes in the balance of excitation and inhibition especially in cortical brain circuits. The effects of shankopathies in activity-dependent brain wiring is an important target for therapeutic intervention. We therefore highlight areas of research consensus and identify remaining questions and challenges.

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

“…Neurogenin 3 is a transcription factor that promotes dendritogenesis in cultured hippocampal neurons [13]. Shank1, along with its family members, are critical scaffolds for postsynaptic density proteins and glutamate receptors, and they are implicated in autism spectrum disorders [14, 15]. The upregulation of these proteins could be a direct effect of TMEM184B or a compensatory effect following other synaptic disruptions; our data does not distinguish between these possibilities.…”

The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders

“…All three SHANK genes ( SHANK1 , SHANK2, and SHANK3 ) are implicated in ASDs, but autistic people with SHANK3 mutations display more severe behavioural deficits [ 156 ]. Animal models targeting ASD-associated Shank mutations exhibit ASD-associated behavioural phenotypes, including impaired sociability and communication, enhanced repetitive self-grooming, and anxiety [ 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 ]. A summary of shankopathies in the developing brain is provided in Table 1 in our recent review [ 195 ].…”

“…Animal models targeting ASD-associated Shank mutations exhibit ASD-associated behavioural phenotypes, including impaired sociability and communication, enhanced repetitive self-grooming, and anxiety [ 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 ]. A summary of shankopathies in the developing brain is provided in Table 1 in our recent review [ 195 ]. Interestingly, many of these animal models demonstrated an alteration in the protein levels of NMDAR subunits, in NMDAR-mediated synaptic transmission, or in synaptic plasticity, such as LTP or LTD [ 106 , 113 , 158 ,…”

Exposure to Antibiotics and Neurodevelopmental Disorders: Could Probiotics Modulate the Gut–Brain Axis?

“…Risk genes involved in the synaptic pathway are found expressed in dendrites, axons, and pre- and postsynaptic terminals, playing different roles [ 21 , 22 ]. There are several genetic mutations found in synaptic genes identified in individuals, encoding for proteins including NLGNs, SHANK2, SHANK3, and CNTNAP2, providing a direct link with the synaptic function and the etiology of NDDs [ 23 , 24 , 25 , 26 , 27 ]. Although recent new technologies favor research advancements in the genetic background of NDDs, they cannot provide information about the environmental influences on genetic predispositions [ 28 , 29 ].…”