Autism-associated Shank3 is essential for homeostatic plasticity and neuronal circuit stability

Abstract

Mutations inShank3 are strongly associated with autism spectrum disorders and 15 circuit disfunction, but a unified view of how Shank3 loss disrupts circuit function and excitability is lacking. Stabilizing, homeostatic forms of synaptic and intrinsic plasticity are critical for preventing circuit hyper-or hypo-excitability, leading us to ask whether Shank3 loss perturbs circuits by disrupting homeostatic plasticity. We show that Shank3 loss abolishes synaptic and intrinsic homeostatic plasticity, which can be rescued by lithium, a 20 drug with therapeutic potential in human Shankopathies. Further, Shank3 loss in vivo

Homeostatic Plasticity Requires Remodeling of the Homer-Shank Interactome

“…Homer1 may drive homeostasis through its interactions with other synaptic proteins in the network that responds to prolonged increases in network activity, including the Shank family of scaffolding proteins. Human SHANK3 is disrupted in an ASD-associated syndrome called Phelan-McDermid Syndrome (Phelan and McDermid, 2012;Wilson et al, 2003) and has been suggested to play a role in homeostatic plasticity in vitro and firing rate recovery in the mouse visual cortex after visual deprivation (Tatavarty et al, 2018). To determine if Shank3, like Homer1, is required for PIN rearrangements observed after whisker trimming, we trimmed the whiskers on one side of Shank3B KO mice (Peça et al, 2011) and measured PiSCES by QMI.…”

“…The barrel cortex, which receives tactile input from the whiskers, is a particularly appropriate region to model ASD, given that atypical sensory processing and tactile sensitivity are hallmarks of ASD (Goel and Portera-Cailliau, 2019). Several recent reports have suggested that homeostatic plasticity is altered in some ASD syndromes (Bülow et al, 2019;Tatavarty et al, 2018). Given that E/I imbalance is a mechanism for homeostasis in the barrel cortex, it is especially intriguing that several mouse models of ASD exhibit altered homeostasis in the barrel cortex (Antoine et al, 2019), and that deletion of two different ASD genes in mouse peripheral somatosensory neurons resulted in aberrant tactile sensitivity associated with reduced presynaptic inhibition of primary somatosensory neurons (Orefice et al, 2016).…”

Shaping Diversity Into the Brain’s Form and Function

“…While a reduction in gray matter volume has been found in the cerebellum, hippocampus, amygdala, and parietal lobe of children with autism spectrum disorder (ASD), others have reported an overall increase in brain volume as a hallmark feature of ASD ( Carlisi et al, 2017 ; Riddle et al, 2017 ). Studies on the underlying genes associated with ASD pathogenesis suggest that a range of functions are disrupted such as synaptic maintenance and motor control ( Antoine et al, 2018 ; Golden et al, 2018 ; Tatavarty et al, 2018 ). However, inconsistent structural findings and the seemingly endless number or combination of genetic causes have complicated the process of studying function in autism and other diseases.…”

Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour

“…An in vivo study has shown that loss of Shank3 led to impairment in the ability of visual cortical circuit recovery following sensory input deprivation [316]. Also, the homeostatic plasticity of neuronal circuits was disrupted in the Shank3 KO model, which hints towards perturbation of the critical period in Shank3 mutation [316].…”

“…An in vivo study has shown that loss of Shank3 led to impairment in the ability of visual cortical circuit recovery following sensory input deprivation [316]. Also, the homeostatic plasticity of neuronal circuits was disrupted in the Shank3 KO model, which hints towards perturbation of the critical period in Shank3 mutation [316]. However, using a conditional knockin mouse model, Mei et al [317] showed re-expression of SHANK3 in adulthood restored spine density and synaptic functions in the striatum.…”