Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models.

Major depressive disorder (MDD) is a common but debilitating mental disorder, affecting an estimated 3.8% of the population worldwide [] and becoming the second-leading contributor to chronic disease burden in the past few decades []. MDD is typically characterized by a loss of interest in previously-rewarding activities and persistent despair, a major contributing factor to suicide []. It was reported in 2023 that more than 700,000 deaths result from suicide every year and that the highest mortality of unnatural causes was depression (30%) [, ]. The primary method of medically countering MDD’s devastating effects is the use of different classes of antidepressants; these include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs). These drugs are understood to relieve depressive symptoms by increasing the availability of neurotransmitters, particularly serotonin (a.k.a., 5-HT), norepinephrine, and dopamine, in the central nervous system (CNS) []. Systematic reviews have shown that the response rates of all these antidepressants are around 50%, and several weeks are required for the effective onset of therapeutic effects [, ]. Simultaneously, several non-pharmacological modalities for more direct neuromodulation have also been under development, with some showing promise as alternative treatments for depression, particularly for patients unresponsive to antidepressant drugs. Some methods have obtained approval from the United States Food and Drug Administration (FDA), including electroconvulsive therapy (ECT), vagus nerve stimulation (VNS) (only for adults), and transcranial magnetic stimulation (TMS) []. While these approaches offer possible symptomatic relief to patients who cannot be helped pharmacologically, they each have important limitations, such as the risk of cognitive impairment or even long-lasting memory loss [], surgical invasiveness [], and long initiation time or even no response []. An important factor contributing to the generation of such side-effects is the inability to accurately target the neuromodulation to specific neuronal populations [, ]. This insight has led to newer neuromodulation techniques being specifically targeted at specific cell types or circuits that are abnormally altered in pathological states. An optogenetic approach that selectively activated excitatory neurons in the medial prefrontal cortex (mPFC - a central hub for processing cognitive and emotional information []), which project to the dorsal raphe nucleus (DRN, the major source of serotonin in the brain []) was shown to rapidly reverse despair-like states in rodents []. This study also implicated the neuronal pathway from the mPFC to the DRN as a potential intervention target for alleviating depression-related behaviors []. However, owing to the opacity of brain tissue, optogenetics requires optical fibers to be invasively implanted into the targeted brain regions to deliver light locally for the entire duration of the treatment, which hampers its clinical translation []. A neuromodulation method capable of combining the advantages of improved targeting - predictable and controllable antidepressant effects with rapid action and minimal side-effects - with greater non-invasiveness and fine spatiotemporal resolution could significantly accelerate the development of next-generation treatments. Sonogenetics - a method analogous to optogenetics - uses low-intensity ultrasound to non-invasively manipulate specific neuronal populations and circuits by genetically inducing them to overexpress ultrasound-sensitive ion channels [–]. This recently-developed strategy is capable of manipulating neuronal activities and neurotransmitter release in specific neuronal populations and neural circuits [–]. Specifically, sonogenetics can affect mesoscale circuits, even in deeper brain regions, such as the ventral tegmental area (VTA)-nucleus accumbens (NAc) dopaminergic projection pathway []. This approach requires only the initial invasive delivery of genetic agents to the brain, while all subsequent ultrasound treatments are external. Moreover, by using ultrasound and microbubbles to open the BBB for AAV delivery, even this initial step could be rendered non-invasive, potentially paving the way for a fully non-invasive protocol. This offers a potential method of disease management with the added merits of non-invasiveness, selectivity, deep penetration, and fine spatiotemporal resolution []. However, this research is still in its early stages, and the feasibility and effectiveness of this approach, particularly with regard to depression-related circuitry, has not yet been comprehensively demonstrated in vivo. Putting together these facts, we hypothesized that a sonogenetic neuromodulation approach could be an effective candidate for non-invasively modulating depression-related circuitry, activating exci