632. EFFECTS OF TENEURIN-4 KNOCKDOWN IN THE PREFRONTAL CORTEX ON DEPRESSIVE BEHAVIORS IN MICE

Abstract Background The number of patients with depression is increasing worldwide; however, current antidepressants need over two weeks for their effect. Around 30% of patients exhibit treatment resistance. Novel therapeutic strategies are required for these problems. Mutation in ODZ4, which encodes the Teneurin-4 (Tenm-4) protein, has been reported as a risk factor for mental disorders such as bipolar disorder and schizophrenia, accompanied by depressive syndrome. In addition, Tenm-4 could induce changes in synapse formation, axon guidance, or cell differentiation in oligodendrocytes. The prefrontal cortex (PFC) is involved in the regulation of depressive behaviors. Aims & Objectives To reveal the relation of Tenm-4 with mental disorders, we generated PFC-specific knockdown (Tenm-4KD) mice and evaluated behavior phenotypes. To investigate neuropathological changes in PFC caused by Tenm4KD, the change in the amount of myelin sheath was evaluated with immunohistochemistry. Method We generated prefrontal Tenm-4KD mice with adeno-associated virus injection male C57BL6/J (6-7 week-old) with (Tenm-4KD, and Mock as control) vectors integrated with the CRISPR-Cas9 system. Four weeks after the AAV injection, behavioral tests, including the sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST), were conducted to assess depression-like behaviors. Additionally, aripiprazole (APZ), a dopamine D2/3 partial agonist and serotonin 5-HT1A partial agonist/5-HT2A antagonist, was administered to evaluate its antidepressant effects. Myelin alterations in the PFC were analyzed using immunofluorescence staining for myelin basic protein (MBP). Results Tenm4KD mice exhibited significant reductions in sucrose preference (Tenm4KD mice=72.1% vs. Mock mice=85.8%, p < 0.05) in SPT. Tenm4KD mice showed increased immobility time in TST (164.7 sec vs. 130.1 sec, p < 0.05) and FST (218.7 sec vs. 179.2 sec, p < 0.01) compared to Mock mice. APZ treatment restored sucrose preference (80.5% vs. 58.6%, p < 0.05) in Tenm4KD mice compared to saline treatment. Furthermore, MBP staining revealed a significant reduction in myelin she in the PFC of Tenm4KD mice. Discussion & Conclusions These results suggest that PFC-specific Tenm4KD induces depression-like behaviors without affecting locomotor activity or recognition memory. The reversal of these behaviors after administration with APZ was recovered, therefore Tenm-4KD could involve dysfunction of dopamine and/or serotonin nervous. Additionally, the observed myelin reduction indicates that Tenm-4 deficiency would contribute to depression pathophysiology through glial dysfunction. Our results suggest PFC-specific Tenm-4KD mice could be a novel model for depression leading to the development of new antidepressant strategies.