REDUCED AMPA RECEPTORS IN THE CEREBELLUM INDUCES BIPOLAR MANIA VIA THE VENTRAL TEGMENTAL AREA

Bipolar disorder is a mental health condition that causes large mood swings, including mania and depression, leading to lower social functioning and quality of life (Nevarez-Flores et al., 2019) and resulting in a large economic burden (Jin and Mosweu, 2017, Bessonova et al., 2020). However, the biological basis, such as synaptic and circuit alterations, underlying bipolar disorder remains unclear. Animal models based on synaptic phenotypes observed in living patients are useful for understanding the circuit mechanisms underlying psychiatric disorders, including bipolar disorder. Excitatory glutamate α- amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission.

However, there has been no technology to visualize AMPARs in the living human brain, which has resulted in a lack of robust biological characterization of the synapse in living patients with psychiatric disorders. Thus, understanding the biological characteristics of synapses in patients with psychiatric disorders, including bipolar disorder, in humans has long been desirable. This study aims to address this knowledge gap and elucidate the biological/synaptic substrate of bipolar disorder.

We have developed a positron emission tomography (PET) tracer for AMPARs, [11C]K-2, which is the first technology used to visualize and quantify the density of AMPARs in the living human brain (Miyazaki et al., 2020). Furthermore, PET imaging with [11C]K-2 (AMPAR PET imaging) depicts cell-surface AMPARs, a functionally crucial fraction of AMPARs (Arisawa et al., 2021). In this study, we PET-scanned 37 patients with bipolar disorder using [11C]K-2 and reported the synaptic phenotypes of bipolar disorder. To examine the causal relationship between the synaptic phenotypes of the patients and the expression of the manic state, we used a reverse-translational (trans-species) approach, i.e., we knocked down AMPAR expression in the mouse brain using short hairpin RNA targeting AMPAR and observed the behavioral phenotypes. Circuit-specific activation using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was also used to identify crucial brain circuits underlying bipolar mania.

In human PET study, we identified brain regions with a significant correlation between AMPAR density and symptomatology scores in bipolar disorder. Among these regions, we detected a significant strong negative correlation between the symptomatology score for the manic state and the density of AMPAR in the cerebellum. In a subsequent animal experiment, reduction of AMPAR in the cerebellum induced a mania-like behavior in mice such as reduced immobility time in forced swim and tail suspension tests, hedonia-like high sucrose preference, and circadian disruption. Furthermore, DREADD experiments identified activation of input from the deep cerebellar nuclei (DCN) to the ventral tegmental area (VTA) pathway was responsible for the expression of the manic state.

Here, we identified crucial brain regions and circuits underlying bipolar mania based on AMPAR using a trans-species approach. Our approach to psychiatric disorders using [11C]K-2 in combination with animal experiments can elucidate the biological mechanisms underlying psychiatric disorders and pave the way for the development of novel diagnostics and therapeutics based on synaptic physiology.

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