Voltage-Gated Ca2+ Channels in Prefrontal Parvalbumin Neurons Are Essential for Stress-Induced Depression

Stress is a risk factor for neuropsychiatric disorders, including depression. While acute stress responses are typically protective and adaptive, prolonged or chronic stress can lead to lasting alterations in brain function that contribute to maladaptive behaviors. Among the brain regions affected by chronic stress, the prefrontal cortex (PFC) stands out due to its critical role in regulating affect, cognition, and top-down control of limbic circuits. Studies with rodent models show that chronic stress induces dendritic retraction, synaptic loss, and disruptions in excitatory/inhibitory (E/I) balance within the PFC [1-3]. These findings parallel neuroimaging studies in humans showing reduced PFC volume and hypoactivity in individuals with stress-related disorders, including major depressive disorder and post-traumatic stress disorder [4, 5]. While disruption of parvalbumin-expressing (PV+) inhibitory GABAergic neurons has been found to drive some of the effects of chronic stress on anxiety- and depressive-like behaviors in rodents [2, 6, 7], the molecular mechanisms linking stress-induced GABAergic dysfunction to long-term behavioral consequences have yet to be fully understood. In a recent issue of Acta Physiologica, Yabuki et al. [8] propose a novel understanding of the molecular mechanisms underlying chronic-stress induced depression using a rodent model.

The authors investigate the role of Cav3.1 T-type calcium channels, located on PV+ neurons in the medial PFC (mPFC), in stress-induced behavioral changes. Using Cav3.1 knockout mice, they demonstrate that deletion of the Cav3.1 channel prevents the development of depressive-like behaviors typically induced by acute stress paradigms such as the forced swim test (FST) and tail suspension test (TST). While these assays are conventionally used to assess acute stress responses, they are leveraged here to measure chronic stress-induced depressive-like behaviors. Stress-induced immobility was abolished in Cav3.1-deficient mice, indicating that Cav3.1 channels are necessary for inducing such depressive-like behavioral phenotypes.

To further probe the underlying neural mechanisms, the authors employed transcriptomic profiling of the mPFC, which revealed that chronic stress alters the expression of genes involved in E/I balance and synaptic signaling in wild-type mice, but not Cav3.1 knockout mice. These changes were particularly pronounced in genes associated with GABAergic transmission, implicating Cav3.1 in modulating the effects of chronic stress on inhibitory circuits in the mPFC.

Electrophysiological recordings demonstrated that chronic stress enhances the excitability of PV+ GABAergic neurons in the mPFC of wild-type mice, but not in Cav3.1-deficient mice, providing a mechanistic link between Cav3.1 channel activity, interneuron excitability, and behavioral output. Optogenetic activation of PV+ neurons in the mPFC was sufficient to induce depressive-like behaviors even in the absence of stress, further confirming the causal role of PV+ neuron hyperactivity in driving maladaptive affective states. Conversely, pharmacologically antagonizing Cav3.1 protected against both the physiological and behavioral consequences of chronic stress.

These findings provide compelling evidence that Cav3.1 channels, through their role in regulating PV+ neurons excitability, are essential for the presentation of stress-induced behavioral deficits (Figure 1), adding to the broader literature on how calcium channel dynamics influence affective behavior. However, it would be important to investigate the underlying neurobehavioral mechanisms that link Cav3.1 channels to the response to repeated stressors. Indeed, the authors chose a chronic stress paradigm that repeatedly exposes mice to the same stressor, likely involving a learning component. T-type calcium channels, including Cav3.1, have been implicated in synaptic plasticity and learning-related processes such as long-term potentiation (LTP) in cerebellar circuits [9, 10]. These processes are foundational for learning and memory, raising the possibility that the observed behaviors may reflect, at least in part, altered cognitive processing or maladaptive learning mechanisms in response to repeated exposure to a stressor, rather than purely depressive-like states. This interpretation is particularly relevant given the behavioral assays employed (FST and TST) are now more recognized as tests to measure coping strategies, and repeated exposure in these paradigms is known to induce behavioral habituation or learned helplessness over time [11, 12]. Thus, it should be further considered whether increased immobility in these paradigms reflects the formation of passive coping strategies that could be more adaptive after repeated exposures, rather than a depressive phenotype.

To strengthen the translational relevance of the findings and more precisely define the role of Cav3.1 T-type channels in stress-induced emotional deregulations, it would be beneficial to incorporate a validated chronic stress model, such as chronic unpredictable stress (CUS), and include assays that capture the multiple facets of depression. CUS is a well-established model that reflects the dynamic nature of real-world stress exposure, while also minimizing the confounding effects of behavioral habituation and learning often introduced by repeated-stressor models. Additionally, the use of a comprehensive set of assays to investigate different aspects of depression, such as anhedonia, social withdrawal, or reduced self-care, could strengthen the interpretation of the behavioral outcomes. Together, these approaches would provide a more comprehensive understanding of the role Cav3.1 plays in stress-induced behavioral adaptation. These complementary approaches would help clarify whether Cav3.1 disruption broadly confers stress resilience or specifically impairs certain forms of stress-induced behavioral adaptation, providing a more comprehensive understanding of its role in affective disorders.

To conclude, Yabuki et al. demonstrate that Cav3.1 channels act as key mediators of GABAergic signaling under stress and are necessary for the emergence of depressive-like behaviors following repeated stress exposure. Their findings add to the growing body of research that aims at uncovering the molecular mechanisms by which chronic stress leads to brain and behavioral dysfunction. Importantly, this study identifies the Cav3.1 T-type calcium channel as a promising therapeutic target for mitigating the long-term effects of psychological stress. While further research is needed to fully understand how Cav3.1-mediated signaling integrates within broader prefrontal circuits, this work introduces valuable new insights into how calcium channel dynamics in the mPFC shape susceptibility to stress-related mood disorders.

Katrina Lin: writing – original draft, writing – review and editing. Laurence Coutellier: writing – original draft, writing – review and editing.

The authors declare no conflicts of interest.