A loss of function of Shank3, a scaffolding protein at excitatory synapses, is associated with autism spectrum disorder (ASD) (Betancur and Buxbaum, Mol. Autism, 2013). Animal models of Shank3 loss have revealed various changes in synaptic function and an imbalance between excitation and inhibition within brain circuits (Lee et al., Front. Cell Neurosci., 2015; Speed et al., J. Neurosci., 2015). However, the cellular mechanisms that underlie these deficits are not yet fully understood. Understanding Shank3 function in the brain is critical for gaining insight into forms of ASD linked to Shank3 mutations. Typically, Shank3 may play a role in compensatory mechanisms — known as homeostatic plasticity mechanisms — that maintain stable function in the developing brain in the face of destabilizing challenges and changes (Turrigiano and Nelson, Nat. Rev. Neurosci., 2004). In a recent study supported in part by a SFARI Research Award, SFARI Investigator Gina Turrigiano and her colleagues further explored how Shank3 mediates synaptic plasticity and showed that changes in phosphorylation state are important in this process (Wu et al., eLife, 2022).

One type of homeostatic plasticity mechanism in the brain, termed synaptic scaling, allows excitatory synapses to increase (scale up) or decrease (scale down) their strength in response to changes in neuronal activity, which ultimately helps maintain the proper excitation–inhibition balance within brain circuits. Shank3 is essential for synaptic scaling up, as previously demonstrated by Turrigiano and her colleagues (Tatavarty et al., Neuron, 2020). In their recent study, they used mass spectrometry–based proteomics in rodent neocortical neurons to show that Shank3 can be phosphorylated and dephosphorylated to regulate homeostatic synaptic plasticity in both directions. Their findings revealed that hypophosphorylation of Shank3, through a process dependent on protein phosphatase 2A, is critical for maintaining increased postsynaptic strength during scaling up and that the function of Shank3 is dynamically modulated by its phosphorylation state to switch it from scaling up to scaling down. These findings offer clues as to how Shank3 loss could contribute to synaptic and circuit dysfunction in the brains of individuals with ASD.