| First Author | Zhuang L | Year | 2024 |
| Journal | Biol Psychiatry | Volume | 95 |
| Issue | 5 | Pages | 389-402 |
| PubMed ID | 37678540 | Mgi Jnum | J:347874 |
| Mgi Id | MGI:7625731 | Doi | 10.1016/j.biopsych.2023.08.026 |
| Citation | Zhuang L, et al. (2024) LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIalpha and ERK. Biol Psychiatry 95(5):389-402 |
| abstractText | BACKGROUND: LHPP was recently shown to be a risk gene for major depressive disorder. LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown about how LHPP contributes to depression. METHODS: In the current study, we addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing, and electrophysiology. RESULTS: We found that levels of LHPP were upregulated in glutamatergic neurons of the ventral hippocampus in mice that displayed stress-induced depression-like behaviors. Knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPP(flox/flox).CaMKIIalphaCre+ (conditional knockout) mice. Adeno-associated virus-mediated LHPP knockdown in the ventral hippocampus enhanced resistance against chronic social defeat stress in mice. Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF (brain-derived neurotrophic factor) and PSD95 via the modulation of the dephosphorylation of CaMKIIalpha and ERK. Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIalpha/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP upregulation-induced depression-like behaviors. CONCLUSIONS: These findings provide evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, thereby identifying LHPP as a potential therapeutic target in treating patients with major depressive disorder. |
