Table 2 Examples of potential convergent biological mechanisms in catatonia and NDDs.

Genetic

Noncoding single nucleotide variants

• Small nucleolar RNA mutations are hypothesized to impact downstream gene regulation & splicing in catatonia⁴⁵

• Mouse models with small nucleolar RNA deletions recapitulate symptoms of autism⁴⁶

Structural variants

• 22q13.3 and 22q11.2 deletions are associated with catatonia³⁹

• Disruption of 22q13.3 and 22q11.2 deletions associated with NDDs¹¹²

Neural circuits

EI imbalance

• Local glutamate overactivity and GABA underactivity is thought to play a role in catatonia^34,52

• Mouse models support disruption in EI balance leading to ASD phenotypes. Increasing EI balance in prefrontal cortex using optogenetics leads to social deficits^61,62

• Decreased GABA receptor density and altered GAD1 and GAD2 levels. Functional imaging studies identify local hyperconnectivity and decreased long-range connections⁶⁰

Neuroimmune interface

Autoimmunity

• NMDAR encephalitis is causally linked to the development of catatonia⁵²

• Systemic autoimmune conditions, like SLE, increase risk for the development of catatonia¹¹³

• Rodent models suggest that brain inflammation in catatonia is mediated by microglial activation³⁷

• Standard treatments for catatonia, like ECT, have been shown to have an immunomodulatory effect over chronic administration⁷¹

• Family history of autoimmune conditions increase the risk for ASD⁶⁵

• Gene network analysis identify immune dysregulation and microglial activation as key molecular signatures⁷⁷

• Rodent models suggest that attenuation of microglial activity can rescue ASD-like behaviors³⁷