Marceau-Linhares, C. | Search bioRxiv

bioRxiv2025

Auditory Brainstem Development in Autism: From Childhood Hypo-Responsivity to Adult Hyper-Reactivity

BackgroundAutism Spectrum Disorder (ASD) is characterized by sensory disruptions, including auditory processing differences, which can significantly impact social, emotional, and cognitive development. This study investigates auditory brainstem development in Autistic children and adults using auditory brainstem responses (ABRs) and acoustic startle responses (ASRs), two key measures of auditory processing. We hypothesize that early hypo-responsivity in children, measured with ABRs, may lead to compensatory neural adaptations, resulting in hyper-reactivity in adulthood, measured by ASRs. MethodsThe study included 40 Autistic children, 57 non-Autistic children, 20 Autistic adults, and 21 non-Autistic adults. Participants underwent peripheral hearing screening, ABR testing at slow and fast click-rates, and ASR measurements. ABR wave and ASR amplitude were analyzed. Statistical analyses included mixed-model ANOVAs and Spearmans correlations to examine group differences and associations with age. ResultsAutistic participants showed trending differences in auditory brainstem timing relative to non-autistic participants, with no differences in brainstem amplitude at any wave or rate. Post hoc slope comparisons revealed that non-Autistic participants showed positive developmental trajectories in Wave I latency at both rates, while Autistic participants showed flat trajectories, a pattern directionally consistent with developmental convergence. A sex-specific group difference was observed at Wave I slow rate, with Autistic females showing longer latencies than non-Autistic females (d = 1.69), with no difference in males. In contrast, ASR amplitude showed diverging developmental trajectories between groups, with Autistic participants showing a positive age-related increase and non-Autistic participants showing a negative age-related decrease (slope contrast: t(99) = 2.16, p = .033, 2p = .05), consistent with a group difference emerging in adulthood. ABR amplitude was positively correlated with ASR amplitude in non-Autistic participants (Wave I: rho = +0.30; Wave V: rho = +0.25) but negatively correlated in Autistic participants (Wave I: rho = -0.19; Wave V: rho = -0.20), with the between-group difference in correlation direction surviving FDR correction for both waves (Fishers z padj = .035). ConclusionThe findings are consistent with the hypothesis that Autistic children experience auditory brainstem hypo-responsivity, which may normalize in adulthood but lead to maladaptive hyper-reactivity. These results highlight the role of early auditory disruptions in shaping long-term sensory processing and reactivity in Autism, emphasizing the need for further research into the neural mechanisms underlying these differences.

neuroscience↗

bioRxiv2024

Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model

BackgroundDysregulated Tau phosphorylation (p-Tau) is a hallmark of neurodegenerative disorders such as Alzheimers disease (AD) or frontotemporal dementia (FTD), resulting in neurofibrillary tangle accumulation, neuronal atrophy and cognitive impairment. Impaired somatostatin (SST) expression and reduced SST-expressing GABAergic neurons significantly contributes to AD-related pathophysiology and correlates with cognitive impairment. SST+ interneurons inhibit the dendrites of excitatory neurons in cortical layers and hippocampus, primarily through 5-GABA-A receptors, regulating cognitive function. Leveraging a newly developed small molecule that targets the 5-GABA-A receptors via positive allosteric modulation (5-PAM), we assessed its effects on p-Tau-related neuronal morphology, cognitive deficits and protein expression. MethodsIn the PS19 transgenic mouse model, we administered the 5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months, corresponding to early and advanced stage of p-Tau accumulation. Golgi staining analyzed dendritic morphology and spine density in mice chronically exposed to 5-PAM. Western blotting was used to quantify p-tau and Tau expression. Spatial working memory was assessed using the Y-maze. ResultsChronic treatment at 3 and 6 months mitigated p-Tau-induced loss of spine density and reduced dendritic length. 5-PAM treatment did not affect p-tau levels. 5-PAM effectively reversed spatial working memory deficits induced by p-tau accumulation both acutely and chronically. Conclusions5-GABA-A receptor positive allosteric modulation displayed neurotrophic (spine and dendritic pathology) and procognitive (working memory) effects in the PS19 model, independently of p-Tau burden. This suggests a novel therapeutic strategy for p-Tau-related pathologies with both symptomatic and disease-modifying potential.

neuroscience↗