AKAP11 links autophagy to cognitive impairment in psychiatric diseases.

Schizophrenia (SCZ) and bipolar disorder (BD) share genetic risk factors and cognitive impairments, yet the underlying mechanisms remain incompletely understood. Loss-of-function variants in AKAP11 (A-kinase anchoring protein 11) have recently emerged as major risk factors for both disorders. Our recent study demonstrates that AKAP11 deficiency in the mouse hippocampus causes cognitive deficits and synaptic dysfunction, accompanied by autophagy dysregulation. Mechanistically, AKAP11 interacts with PPP3CB (protein phosphatase 3 catalytic subunit beta) to promote TFEB (transcription factor EB) dephosphorylation and nuclear translocation, thereby sustaining autophagy-lysosomal gene expression. AKAP11 knockout cells display impaired autophagy initiation, reduced lysosomal activity, and compromised autophagic flux. Therapeutically, pharmacological activation of TFEB rescues cognitive deficits in Akap11-deficient mice. These findings position AKAP11 as a critical regulator of TFEB-mediated autophagy and suggest that enhancing autophagy-lysosomal function may represent a therapeutic strategy for SCZ and BD.