The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder

Ho Namkung; Hiroshi Yukitake; Daisuke Fukudome; Brian J Lee; Mengnan Tian; Gianluca Ursini; Atsushi Saito; Shravika Lam; Suvarnambiga Kannan; Rupali Srivastava; Minae Niwa; Kamal Sharma; Peter Zandi; Hanna Jaaro-Peled; Koko Ishizuka; Nilanjan Chatterjee; Richard L Huganir; Akira Sawa

doi:10.1016/j.neuron.2022.10.031

The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder

Neuron. 2023 Jan 18;111(2):220-235.e9. doi: 10.1016/j.neuron.2022.10.031. Epub 2022 Nov 14.

Authors

Ho Namkung¹, Hiroshi Yukitake², Daisuke Fukudome², Brian J Lee², Mengnan Tian³, Gianluca Ursini⁴, Atsushi Saito², Shravika Lam⁵, Suvarnambiga Kannan⁶, Rupali Srivastava², Minae Niwa², Kamal Sharma⁵, Peter Zandi⁷, Hanna Jaaro-Peled², Koko Ishizuka², Nilanjan Chatterjee⁸, Richard L Huganir⁹, Akira Sawa¹⁰

Affiliations

¹ Department of Biomedical Engineering, Baltimore, MD, USA; Department of Psychiatry, Baltimore, MD, USA.
² Department of Psychiatry, Baltimore, MD, USA.
³ Department of Neuroscience, Baltimore, MD, USA.
⁴ Department of Psychiatry, Baltimore, MD, USA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
⁵ Department of Psychiatry, Baltimore, MD, USA; Department of Neuroscience, Baltimore, MD, USA.
⁶ Department of Psychiatry, Baltimore, MD, USA; Department of Mental Health, Baltimore, MD, USA.
⁷ Department of Psychiatry, Baltimore, MD, USA; Department of Mental Health, Baltimore, MD, USA; Department of Epidemiology, Baltimore, MD, USA.
⁸ Department of Epidemiology, Baltimore, MD, USA; Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁹ Department of Psychiatry, Baltimore, MD, USA; Department of Neuroscience, Baltimore, MD, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
¹⁰ Department of Biomedical Engineering, Baltimore, MD, USA; Department of Psychiatry, Baltimore, MD, USA; Department of Neuroscience, Baltimore, MD, USA; Department of Pharmacology, Baltimore, MD, USA; Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Mental Health, Baltimore, MD, USA. Electronic address: asawa1@jhmi.edu.

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.

Keywords: AMPAR; bipolar disorder; miR-124; polygenic risk; schizophrenia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bipolar Disorder* / genetics
Bipolar Disorder* / metabolism
Mice
MicroRNAs* / genetics
MicroRNAs* / metabolism
Multifactorial Inheritance
Prefrontal Cortex / metabolism
Schizophrenia* / genetics
Schizophrenia* / metabolism

Substances

MicroRNAs
Mirn124 microRNA, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding