Tanc2, a large multi-domain postsynaptic scaffold protein, is mainly expressed in the brain [2]. It interacts with multiple postsynaptic density (PSD) proteins, playing essential roles in synaptic transmission, dendrite formation in synaptic plasticity, and is involved in regulating dendritic spines and excitatory synapse formation [1,3,6]. Tanc2 also has a direct inhibitory effect on mTOR, balancing mTORC1/2 signaling which critically regulates neural development [4].

In zebrafish, tanc2 knockout leads to an increase in larval brain size and body length, an excitatory/inhibitory (E/I) imbalance with more glutamatergic neurons, sleep disturbance in larvae, and autism-like behaviors such as anxiolytic-behavior, reduced aggression, and impaired social preference in adults [2]. In mice, Tanc2-null mice show embryonic lethality, while Tanc2-haploinsufficient mice display mTORC1/2 hyperactivity, synaptic and behavioral deficits that can be reversed by mTOR-inhibiting rapamycin [4]. In Drosophila, knockdown of TANC2 leads to increased susceptibility to seizure-like behavior [5].

In conclusion, Tanc2 is crucial for neurodevelopment, with its disruption leading to various neurodevelopmental and psychiatric disorders such as autism, intellectual disability, epilepsy, and sleep disturbances as demonstrated by gene knockout models in different species. These models have provided valuable insights into the role of Tanc2 in these disease conditions, highlighting its significance in understanding the underlying mechanisms of related disorders.