Shank2, coding a scaffolding protein, is located at the postsynaptic membrane of glutamatergic neurons. It is involved in multiple biological processes and has been linked to neurodevelopmental and neuropsychiatric disorders [1,6]. It may also play a role in regulating the Hippo pathway, which is related to cancer development [4].

In animal models, Shank2 -/- mice show increased sensitivity to formalin pain and thermal preference, along with sensory-specific mechanical allodynia. High levels of Shank2 expression identify a sub-population of glycinergic interneurons in the dorsal spinal cord, and loss of Shank2 causes a decrease in NMDAR in excitatory synapses on these inhibitory interneurons, affecting nociceptive processing relevant to autism-like phenotypes [2]. SHANK2 mutations in human-derived neurons lead to hyperconnectivity, with increased dendrite length, complexity, synapse number, and spontaneous excitatory postsynaptic currents [3]. SHANK2 mutant SH-SY5Y cells show impaired neuronal differentiation, with changes in apoptosis, proliferation, and neurite outgrowth, as well as altered downstream signaling of tyrosine kinase receptors and amyloid precursor protein expression [5]. Shank2-knockout mice display impaired reversal learning, potentially due to enhanced fear, indicating that abnormal emotional responses may limit behavioral flexibility relevant to autism spectrum disorder (ASD) [7]. Shank2 knockout in podocytes leads to reduced albumin uptake and proteinuria in mice, suggesting its role in renal albumin endocytosis [8]. Shank2-Shank3 double knockout in the retrosplenial area of mice severely impairs social memory, a core symptom of ASD, and DREADD-mediated neuronal activation can rescue this impairment [9]. Shank2-deficient male mice show reduced single-cued safety learning, which may contribute to emotional symptoms in ASD and its comorbidity with anxiety-related disorders [10].

In summary, Shank2 is crucial for normal neuronal development and function, as well as renal albumin handling. Gene-knockout mouse models have been instrumental in revealing its role in neurodevelopmental and neuropsychiatric disorders such as ASD, anxiety-related disorders, and in understanding nociceptive processing and social memory deficits. These models also help in exploring its function in cancer-related Hippo pathway regulation.