Henry-Duru, P. T. | Search bioRxiv

bioRxiv2025

Cannflavin B ameliorates social and anxiety deficits and neuronal systems dysfunction in adolescent rats exposed to prenatal valproic acid

There has been growing interest in natural products as potential therapeutics for the core and comorbid symptoms of autism spectrum disorders. Almost all the studies on autism have focused on the therapeutic benefits of cannabis and its associated cannabinoids. In this study the potential therapeutic efficacy of cannflavin B, a related, yet non-psychoactive component of the Cannabis sativa plant, was evaluated. Using prenatal valproic acid (VPA) exposure in rats, a model that has been widely used to study aspects of autism, we showed that cannflavin B was anxiolytic in the female VPA rats, and normalized sociality in VPA animals of both sexes. When neuronal oscillatory activity was examined, in female VPA rats cannflavin B normalized alterations in low frequency power within the cingulate cortex (Cg), and theta-gamma cross frequency coupling between the dorsal hippocampus (dHIP) and the prefrontal cortex (PFC). In male VPA animals, cannflavin B induced frequency-specific alterations in power within the PFC, Cg, and dHIP and ameliorated the VPA-induced suppression of oscillatory coherence between all three regions. In each brain region, cannflavin B also attenuated the sex-specific VPA-induced elevations in microglia. In vitro, cannflavin B normalized VPA-induced elevations in cortical and HIP neuronal activity and promoted more organized cortical firing. These findings demonstrate cannflavin B normalizes behavioural and neuronal systems function alterations induced by prenatal VPA in rats. The present study highlights the importance of alternative cannabis compounds in autism and other disorders.

neuroscience↗

bioRxiv2024

Prenatal exposure to valproic acid induces sex-specific alterations in cortical and hippocampal neuronal structure and function in rats

BackgroundThere are substantial differences in the characteristics of males and females with an autism spectrum disorder (ASD), yet there is little knowledge surrounding the mechanistic underpinnings of these differences. The valproic acid (VPA) rodent model is the most widely used model for the study of idiopathic ASD, but almost all of the studies have used male rodents. MethodTo fill this knowledge gap, we evaluated sex differences for neuronal activity, morphology, and glycogen synthase kinase-3 (GSK-3) signaling in primary cortical (CTX) and hippocampal (HIP) neurons prepared from rats exposed to VPA in utero. In vivo, sex-specific VPA-induced alterations in the frontal CTX transcriptome at birth were also determined. ResultsOverall, VPA induced more robust changes in neuronal function and structure in the CTX than in the HIP. Male- and female-derived primary CTX neurons from rats exposed to prenatal VPA had elevated activity and showed more disorganized firing. In the HIP, only the female VPA neurons showed elevated firing, while the male VPA neurons exhibited disorganized activity. Dendritic arborization of CTX neurons from VPA rats was less complex in both sexes, though this was more pronounced in the females. Conversely, both female and male HIP neurons from VPA rats showed elevated complexity distal to the soma. Female VPA CTX neurons also had an elevated number of dendritic spines. The relative activity of the and {beta} isoforms of GSK-3 were suppressed in both female and male VPA CTX neurons, with no changes in the HIP neurons. On postnatal day 0, alterations in CTX genes associated with neuropeptides (e.g., penk, pdyn) and receptors (e.g., drd1, adora2a) were seen in both sexes, though they were downregulated in females and upregulated in males. LimitationsPrimary neuron studies may not recapitulate findings performed in vivo or at later stages of development. ConclusionTogether these findings suggest that substantial sex differences in neuronal structure and function in the VPA model may have relevance to the reported sex differences in idiopathic ASD.

neuroscience↗