P11 Loss-of-Function is Associated with Decreased Cell Proliferation and Neurobehavioral Disorders in Mice

Abstract

Although depression is associated with anxiety and memory deficit in humans, the molecular mechanisms of the complication remain largely unknown. In this study, we generated P11 knockout mice using CRISPR/Cas9 technology, as well as P11 knockout MEF cell lines, and confirmed depression-like phenotype. We observed that knockout of P11 in MEFs led to a decreased cell proliferation compared with P11 +/+ MEFs. Moreover, P11 knockout resulted in a larger cell size, which resulted probably from accumulated F-actin stress fibers. The number of proliferating cells was decreased in the hippocampus of P11 KO mice. We observed anxiety-like disorder in addition to depression phenotype in the knockout mice. In addition, knockout of P11 led to memory deficit in female mice, but not in males. These data indicated that P11 is involved in regulating cell proliferation and cell size. The molecular associations of depression behavior with anxiety and memory deficit suggested a potential approach to improve therapeutic intervention through P11 in these disorders.

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…The use of Cre-driver mouse lines for targeting local specific brain areas associated with depression and emotionality such as forebrain, hippocampus and VTA, provides a new approach to investigate proof of concept as to how the brain modulates mood and mood disorders [ 311 , 312 ]. Within the development of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9) system (CRISPR/Cas9) technology, the new generation of KO mice were developed in order to investigate the role of specific proteins on depression-like phenotype development and for further translation to clinical depression [ 313 , 314 , 315 ].…”

The Nucleus Accumbens: A Common Target in the Comorbidity of Depression and Addiction

“…A small receptor-binding protein p11 is a critical regulator of ChI activity within the NAc, as measured by the DA response to the mesolimbic DA reward stimulus pathway (Hanada et al, 2018 ; Liu et al, 2019 ). p11 is required for reward-mediated NAc ChI activation and the induction of acetylcholine (ACh) release, resulting in the enhancement of DA release (Hanada et al, 2018 ).…”

DNA Methyltransferases in Depression: An Update

“…Recent studies demonstrated that the methylations of some specific genes such as P11 ( 30 – 33 ), BDNF ( 34 – 38 ), SLC6A4 ( 39 – 42 ), and NR3C1 ( 43 – 45 ), were closely correlated to depression. For example, Svenningsson et al found that the P11 knockout mice showed anhedonia-like and despair-like behaviors assessed with above mentioned SCT, TST, and FST ( 33 ).…”