Lafuente, J. V. | Search bioRxiv

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

Sex-specific vulnerability to behavioural and morphological alterations in a mouse model of Parkinson's disease overexpressing mutant A53T alpha-synuclein

Parkinsons disease (PD) is characterised by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and accumulation of misfolded -synuclein (-syn). Neuroinflammation also contributes to disease onset and progression. Notably, PD exhibits sexual dimorphism in clinical presentation and treatment response. This study investigated sex-specific behavioural and morphological changes in a mouse model overexpressing A53T -syn. Male and female C57BL/6J mice received bilateral intranigral injections of adeno-associated viral vectors encoding mutant A53T -syn or empty vectors. Motor function was assessed at 60 and 120 days post-surgery using open field, wire hang, pole, and balance beam tests. Brains were collected for immunohistochemical analyses of -syn pathology, nigrostriatal integrity (tyrosine hydroxylase, TH), axonal degeneration, and neuroinflammation. -Syn overexpression induced early, subtle motor deficits primarily in males, despite preserved SNc neuronal density. Automated analysis of balance beam walking behaviour (DeepLabCut, SimBA) revealed increased immobility and reduced walking time in -syn males. At 120 days only, striatal TH levels were significantly reduced, driven by reductions in -syn males. Although undetected at 60 days, an axonal degeneration index (combining striatal TH optical density and axonal swellings) revealed more advanced degeneration in -syn males, suggesting faster disease progression. At both time points, -syn mice showed increased striatal astrogliosis without sex differences, indicating -syn-associated neuroinflammation. These findings support a PD model of early axonal degeneration and reactive astrogliosis preceding neuronal loss. The sex-specific behavioural and neuropathological patterns underscore the importance of incorporating sex as a biological variable in preclinical models and developing tailored therapeutic strategies.

neuroscience↗