Antidepressants Stimulate Hippocampal Neurogenesis by Inhibiting p21 Expression in the Subgranular Zone of the Hipppocampus

Abstract

The relationships among hippocampal neurogenesis, depression and the mechanism of action of antidepressant drugs have generated a considerable amount of controversy. The cyclin-dependent kinase (Cdk) inhibitor p21Cip1 (p21) plays a crucial role in restraining cellular proliferation and maintaining cellular quiescence. Using in vivo and in vitro approaches the present study shows that p21 is expressed in the subgranular zone of the dentate gyrus of the hippocampus in early neuronal progenitors and in immature neurons, but not in mature neurons or astroglia. In vitro, proliferation is higher in neuronal progenitor cells derived from p21-/- mice compared to cells derived from wild-type mice. Proliferation is increased in neuronal progenitor cells after suppression of p21 using lentivirus expressing short hairpin RNA against p21. In vivo, chronic treatment with the non-selective antidepressant imipramine as well as the norepinephrine-selective reuptake inhibitor desipramine or the serotonin-selective reuptake inhibitor fluoxetine all decrease p21 expression, and this was associated with increased neurogenesis. Chronic antidepressant treatment did not affect the expression of other Cdk inhibitors. Untreated p21-/- mice exhibit a higher degree of baseline neurogenesis and decreased immobility in the forced swim test. Although chronic imipramine treatment increased neurogenesis and reduced immobility in the forced swim test in wild-type mice, it reduced neurogenesis and increased immobility in p21-/- mice. These results demonstrate the unique role of p21 in the control of neurogenesis, and support the hypothesis that different classes of reuptake inhibitor-type antidepressant drugs all stimulate hippocampal neurogenesis by inhibiting p21 expression.

Cyclin-Dependent Kinase Inhibitor 1a (p21) Modulates Response to Cocaine and Motivated Behaviors

“…5A) and there was no significant difference in staining between saline-and cocaine-treated animals in the dorsal hippocampus. Similar to data reported by Pechnick et al (2011), positive p21 staining was present in the subgranular zone of the dentate gyrus (Fig. 5B, black arrows).…”

“…Multiple studies suggest a correlation between adult neurogenesis and learning capability (Shors et al, 2001(Shors et al, , 2002Raber et al, 2004;Winocur et al, 2006;Wojtowicz et al, 2008;Snyder et al, 2009a,b;Deng et al, 2010;Cameron and Glover, 2015), such as that necessary for successful CPP and CPA. Data presented here support the finding by Pechnick et al (2011) that p21 2/2 mice express higher levels of both DCX and NeuN and further demonstrate that these increases are specific to the dorsal hippocampus. In wild-type mice, we note that NeuN expression is higher in the ventral hippocampus relative to the dorsal hippocampus, consistent with lower basal expression of p21 in the ventral sector.…”

“…In fact, neural progenitor cells derived from mice lacking cyclin-dependent kinase inhibitor 1a (Cdkn1a,p21) show higher proliferation than those derived from wild-type mice (Pechnick et al, 2011;Zonis et al, 2013); similarly, suppression of p21 using short hairpin RNA increases neural cell proliferation (Pechnick et al, 2011), suggesting that p21 may regulate neurogenesis. Although studies investigating the role of CDKs and their inhibitors in response to drugs of abuse are limited, published data illustrate a strong potential link between these proteins and cocaine-induced effects.…”

Long-Term Adaptive Changes Induced by Antidepressants: From Conventional to Novel Therapies

“…The requirement of hippocampal neurogenesis for therapeutic efficacy of ADs was subsequently confirmed in non-human primates [103]. Consistent with the time course of their therapeutic action, only chronic treatment regimen with MAOIs [104,105], TCAs [106,107], SSRIs [61,102,105,108], putative fast-acting AD drugs including 5-HT 4 agonists [79] and 5-HT 7 antagonists [71] and finally adjunctive strategies (olanzapine plus fluoxetine) [108] increased the cell proliferation in the SGZ of the hippocampus at comparable extent. This indicates that upregulation of hippocampal neurogenesis may be a common denominator of the mechanism of action of ADs.…”

Neural Mechanisms of Exercise: Anti-Depression, Neurogenesis, and Serotonin Signaling

“…leptin, adiponectin) [66,67], and cell cycle regulation (e.g. inhibiting p21) [68]. Very recently, several studies pointed out a new player in exercise-enhanced adult neurogenesis -serotoninergic signaling.…”