The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder.
Neuron
; 111(2): 220-235.e9, 2023 01 18.
Article
em En
| MEDLINE
| ID: mdl-36379214
ABSTRACT
Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. This study shows the miR-124-3p-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered the upregulation of miR-124-3p in neuronal cells and the postmortem prefrontal cortex from both SZ and BP patients. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124-3p in the medial prefrontal cortex. We demonstrated that the upregulation of miR-124-3p increases GRIA2-lacking calcium-permeable AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
/
Transtorno Bipolar
/
MicroRNAs
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article