Bengoetxea, H. | bioRxiv Science

bioRxiv2026

Differential Effects of 5-HT7 Receptor Signaling in the Noradrenergic System in a Rat Model of Treatment-Resistant Depression

IntroductionTreatment-resistant depression (TRD) is a major clinical challenge, and its neurobiological basis remains unclear. The locus coeruleus (LC), a key noradrenergic hub, shows altered activity in TRD models, and serotonergic 5-HT7 receptors have emerged as potential modulators of this circuit. MethodsWe assessed the impact of 5-HT7 receptor activation on LC function in Wistar Kyoto rats, an established TRD model, using in vivo extracellular recordings, in vitro patch-clamp assays, and receptor expression analysis. ResultsSystemic administration of AS19, a selective 5-HT7 receptor agonist, increased LC neuronal firing in both strains, with a significantly greater effect in Wistar Kyoto rats. This response was prevented by a 5-HT7 antagonist confirming receptor specificity. Glutamatergic blockade altered AS19 effects in a strain-dependent manner, whereas in vitro assays revealed no differential postsynaptic modulation and similar presynaptic inhibition across groups. Western blot analysis showed elevated 5-HT7 receptor expression in the LC, ventral hippocampus, and amygdala of Wistar Kyoto rats, alongside reduced expression in the prefrontal cortex. ConclusionThese findings indicate that 5-HT7 receptor activation exerts complex, circuit-dependent modulation of LC activity, influenced by glutamatergic and serotonergic inputs. Enhanced receptor expression in limbic regions and altered LC responsiveness may contribute to TRD pathophysiology and highlight 5-HT7 signaling as a promising target for novel therapeutic strategies.

neuroscience↗

bioRxiv2025

Locus Coeruleus alpha-Synuclein Overexpression Induces Prodromal Parkinsonian Features in Mice

The locus coeruleus is one of the first brain regions to develop -synuclein pathology during the prodromal phase of Parkinsons Disease, contributing significantly to non-motor symptoms such as cognitive decline, mood alterations or sleep disturbances. However, the precise role of the locus coeruleus in the early stages of the disease remains unclear. To address this, we developed and characterized a novel mouse model based on the PRSx8-driven overexpression of human -synuclein in noradrenergic neurons of the locus coeruleus using an adeno-associated viral vector. Animals were assessed at 1 and 3 months post-injection using an integrated battery of histological, behavioural, neurochemical, and electrophysiological analyses. We observed robust accumulation of phosphorylated -synuclein in the locus coeruleus, along with widespread propagation to projection areas, including the hippocampus, prefrontal cortex, and dorsal raphe. Despite the absence of neuronal loss in the locus coeruleus, we identified reduced noradrenergic axonal integrity and marked decreases in both noradrenaline and serotonin levels, highlighting a disruption of neurochemical balance at an early stage. The electrophysiological data revealed transient alterations in the excitability and intrinsic properties of locus coeruleus neurons in a sex-dependent manner, suggesting that -synuclein pathology induces early functional disruption prior to overt neurodegeneration. Behavioural outcomes demonstrated selective cognitive deficits and mild anxiety-like behaviours, while other non-motor functions remained preserved. Importantly, although several pathological and functional alterations were evident in the initial phases, behavioural impairments were also maintained at later time points, indicating that locus coeruleus-driven pathology exerts long-lasting consequences. Interestingly, female mice exhibited colon shortening, providing evidence of a sex-specific pathological process at the level of the gut-brain axis. We believe that this model accurately replicates key prodromal features of Parkinsons disease, demonstrating that -synuclein-induced pathology in the locus coeruleus leads to functional circuit impairment and cognitive decline. Our findings emphasize the locus coeruleus as a critical site of early vulnerability in Parkinsons Disease and underscore the importance of sex as a biological variable influencing disease progression and therapeutic response.

neuroscience↗