Molecular mechanism for higher brain functions, neuropsychiatric disorders

Takanobu Nakazawa, Specially Appointed Associate Professor at Osaka University, Masanobu Kano, Professor at The University of Tokyo, and Ryota Hashimoto, Associate Professor at Osaka University generated ARHGAP33 knockout (KO) mice to examine the function of ARHGAP33. The research group found impaired spine development and decreased miniature excitatory postsynaptic current frequency and amplitude in ARHGAP33 KO mice. The research group also found that ARHGAP33 KO mice show impaired working memory and prepulse inhibition, both of which related to neuropsychiatric disorders, such as schizophrenia.

Then, the research group examined the molecular mechanism behind the impaired synaptic functions and behaviors in ARHGAP33 KO mice and found that ARHGAP33 is localized to the Golgi apparatus to regulate intracellular protein trafficking of the Tropomyosin receptor kinase B (TrkB) receptor, a neurotrophin receptor, to synaptic sites. Neurotrophins play important roles in the formation and function of synapses. In ARHGAP33 KO mice, TrkB is not sufficiently transported to synaptic sites due to the lack of ARHGAP33, which eventually leads to impaired synaptic functions and behaviors.

Finally, the group found that the human ARHGAP33 is associated with schizophrenia.

The molecular pathophysiology of neuropsychiatric disorders is still not well understood, and the development of new antipsychotic drugs is imperative. The group' finding that the impaired intracellular protein trafficking leads to neuropsychiatric disorders-related abnormal higher brain functions has high impact on the fields of psychiatry, basic medical sciences, and pharmaceutical sciences. This study can potentially contribute to the development of new treatment strategies for neuropsychiatric disorders, such as schizophrenia.