Elevation of p11 in lateral habenula mediates depression-like behavior

• Published in: Molecular psychiatry Vol. 23; no. 5; pp. 1113 - 1119
• Main Authors: Seo, J-S, Zhong, P, Liu, A, Yan, Z, Greengard, P
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2018; Nature Publishing Group UK
• Subjects: Animal models; Animals; Annexin A2 - genetics; Annexin A2 - metabolism; Depression (Mood disorder); Depression - genetics; Depression - metabolism; Depression - physiopathology; Depressive Disorder - metabolism; Depressive Disorder - physiopathology; Development and progression; Diencephalon; Disease Models, Animal; Dopamine D2 receptors; Gene Knockdown Techniques - methods; Habenula; Habenula - metabolism; Habenula - physiology; Health aspects; Hyperactivity; Luteinizing hormone; Male; Mental depression; Mice; Mice, Transgenic; Molecular biology; Molecular chains; Molecular modelling; Nerve tissue proteins; Neurons; Neurons - metabolism; Physiological aspects; Psychiatric research; Receptors, Dopamine D2 - metabolism; S100 Proteins - genetics; S100 Proteins - metabolism; Stress; Up-Regulation
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2017.96

The lateral habenula (LHb) is a key brain region involved in the pathophysiology of depression. It is activated by stimuli associated with negative experiences and is involved in encoding aversive signals. Hyperactivity of LHb is found in both rodent models of depression and human patients with depression. However, little is known about the underlying molecular mechanisms. Here we show that in LHb neurons, p11, a multifunctional protein implicated in depression, is significantly upregulated by chronic restraint stress. Knockdown of p11 expression in LHb alleviates the stress-induced depression-like behaviors. Moreover, chronic restraint stress induces bursting action potentials in LHb neurons, which are abolished by p11 knockdown. Overexpression of p11 in dopamine D2 receptor-containing LHb neurons of control mice induces depression-like behaviors. These results have identified p11 in LHb as a key molecular determinant regulating negative emotions, which may help to understand the molecular and cellular basis of depression.