Abstract
Major depressive disorder (MDD) is a common disorder with a variety of symptoms including mood alterations, anhedonia, sleep and appetite disorders, and cognitive disturbances. Stressful life events are among the strongest risk factors for developing MDD. At the cellular level, chronic stress results in the modification of dendritic spine morphology and density. Here, we study the role of Pyk2 in the development of depressive-like symptoms induced by a model of chronic unpredictable mild stress (CUMS). Pyk2 is a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the forebrain principal neurons and involved in spine structure and density regulation. We show that Pyk2 knockout mice are less affected to anxiety-like and anhedonia-like phenotypes induced by the CUMS paradigm. Using region-specific knockout, we demonstrate that this phenotype is fully recapitulated by selective Pyk2 inactivation in the amygdala. We also show that in the absence of Pyk2 the spine alterations, PSD-95 clustering, and NMDA receptors changes induced by the CUMS paradigm are prevented. Our results reveal a possible role for Pyk2 in the response to stress and in synaptic markers expression and spine density regulation in the amygdala. We suggest that Pyk2 contributes to stress-induced responses through micro-structural changes and that its deficit may contribute to the resilience to chronic stress.
Highlights
Major depressive disorder (MDD) is a debilitating disease characterized by low mood, loss of interest in outside stimuli, impaired cognitive function, and vegetative symptoms, such as disturbed sleep or appetite[1]
We found a significant preference for the open arms of the Pyk2+/+ control mice as compared to the Pyk2+/+:chronic unpredictable mild stress (CUMS) (Fig. 1f)
We showed that in basal conditions the absence of Pyk[2] does not modify the responses in anxiety-like and depression-like behavioral tests, PyK2 ablation in the adult confers a marked resistance to the sequelae induced by CUMS, as shown by the normal performances in the plus maze and sucrose preference tests
Summary
Major depressive disorder (MDD) is a debilitating disease characterized by low mood, loss of interest in outside stimuli, impaired cognitive function, and vegetative symptoms, such as disturbed sleep or appetite[1]. Pyk2−/− and Pyk2−/−:CUMS groups of mice showed a comparable preference for sweet water, with no difference from that observed in control Pyk2+/+ mice. Our analysis confirmed the previous reports showing that dendritic spine density was significantly increased in Pyk2+/+ mice, 10 days after the CUMS protocol, as compared to Pyk2+/+ controls (Fig. 4a, b).
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