Jiawei Sini San ameliorates cognitive deficits in CUMS depression rats by reshaping dendritic spines through...

Depression has emerged as a significant public health concern in recent years. Evidence suggests that aberrant hippocampal synaptic plasticity plays a central role in the cognitive impairment associated with depression. Nevertheless, the precise underlying mechanisms remain poorly understood. Although Jiawei Sini San (JWSNS) has shown significant clinical efficacy in treating depression, its specific role in improving cognitive function requires further investigation.

To elucidate the role and mechanism of JWSNS in enhancing cognitive function and remodeling hippocampal dendritic spines.

The chronic unpredictable stress (CUMS) protocol was used to induce depression-like behavior in rats. A hippocampal TRPC6 knockdown model was then established using adeno-associated virus (AAV) targeting. Following treatment with JWSNS or fluoxetine (FLX), behavioral assays were performed to assess depressive behavior, anxiety, and cognitive impairment. Golgi staining was employed to analyze dendritic spine morphology in hippocampal tissues. Western blotting and immunofluorescence were applied to evaluate markers of the TRPC6-mediated ROCK2-Cofilin signaling pathway. Primary hippocampal cells were transfected with lentivirus to inhibit TRPC6 expression, and a stress model was generated by exposing cells to elevated corticosterone levels. Phalloidin fluorescent staining was used to assess cytoskeletal actin, and the effects of JWSNS drug-containing serum on these processes were further investigated.

JWSNS significantly alleviated depressive- and anxiety-like behaviors and ameliorated cognitive deficits in CUMS-exposed rats. Morphologically, JWSNS promoted dendritic spine remodeling in the hippocampal dentate gyrus and CA1 regions. In vivo experiments demonstrated that JWSNS upregulated TRPC6 expression and activated the downstream ROCK2-Cofilin signaling pathway. Targeted knockdown of TRPC6 precipitated severe dendritic spine loss and inhibition of the ROCK2-cofilin pathway, which were effectively reversed by JWSNS intervention. In vitro, lentiviral knockdown of TRPC6 in primary hippocampal neurons led to a reduction in cytoskeletal F-actin, which was significantly restored by exposure to JWSNS-containing serum.

JWSNS effectively ameliorates depression-associated cognitive deficits by remodeling hippocampal dendritic spines via the TRPC6-ROCK2-Cofilin signaling pathway. These findings not only elucidate the neuroprotective mechanisms of JWSNS but also highlight its promising clinical translational value as an alternative or complementary therapeutic strategy for depression and its associated cognitive impairments.