Neuropsin Inactivation Has Protective Effects against Depressive-Like Behaviours and Memory Impairment Induced by Chronic Stress

Mounting evidence suggests the interaction between stress and genetics contribute to the development of depressive symptoms. Currently, the molecular mechanisms mediating this process are poorly understood, hindering the development of new clinical interventions. Here, we investigate the interaction between neuropsin, a serine protease, and chronic stress on the development of depressive-like behaviours in mice. We found no difference in baseline behaviour between neuropsin knockout and wild-type mice. However, our results show that neuropsin knockout mice are protected against the development of depressive-like behaviours and memory impairment following chronic stress. We hypothesised that this difference in behaviour may be due to an interaction between neuropsin and elevated plasma corticosterone. To test this, we subjected mice to chronic corticosterone injections. These injections resulted in changes to hippocampal structure similar to that observed following chronic stress. We found that inactivation of neuropsin limits the extent of these anatomical changes in both the chronic stress and the corticosterone injection exposed cohorts. We next used viral vectors to knockdown or overexpress neuropsin in the hippocampus to confirm the results of the KO study. Additionally, we found that inactivation of neuropsin limited glutamate dysregulation, associated with increased generation of reactive oxygen species, resulting from prolonged elevated plasma corticosterone. In this study, we demonstrate that neuropsin inactivation protects against the impairment of hippocampal functions and the depressive-like behaviour induced by chronic stress or high levels of corticosterone. Consequently, we suggest neuropsin is a potential target for clinical interventions for the management of stress disorders.

越来越多的证据表明，压力与遗传因素的相互作用会促使抑郁症状的发生发展。目前，介导这一过程的分子机制尚不明确，这阻碍了新型临床干预手段的研发。本研究针对丝氨酸蛋白酶（serine protease）神经素（neuropsin）与慢性压力的相互作用对小鼠类抑郁行为发生发展的影响展开探究。我们发现，神经素基因敲除（knockout）小鼠与野生型（wild-type）小鼠的基线行为并无显著差异。但实验结果显示，慢性压力暴露后，神经素基因敲除小鼠可免受类抑郁行为与记忆损伤的影响。我们推测，该行为差异可能源于神经素与血浆皮质酮（corticosterone）水平升高之间的相互作用。为验证这一假说，我们对小鼠进行了慢性皮质酮注射处理，该操作可引发海马体（hippocampus）结构改变，其变化与慢性压力暴露后观察到的结果相似。我们发现，在慢性压力暴露组与皮质酮注射暴露组中，神经素失活均可限制这类解剖学变化的程度。随后，我们通过病毒载体（viral vectors）在小鼠海马体中敲低或过表达神经素，以验证基因敲除实验的结果。此外，我们还发现，神经素失活可抑制由血浆皮质酮长期升高所引发的谷氨酸（glutamate）失调，以及伴随而来的活性氧（reactive oxygen species）生成增多。本研究证实，神经素失活可抵御慢性压力或高皮质酮水平所诱导的海马体功能损伤与类抑郁行为。综上，我们认为神经素可作为应激障碍临床干预的潜在靶点。