Wollet, M. | bioRxiv Science

bioRxiv2024

Impacts of Perinatal Nicotine Exposure on nAChR Expression and Glutamatergic Synaptic Transmission in the Mouse Auditory Brainstem

Exposure to nicotine in utero, often due to maternal smoking, significantly elevates the risk of auditory processing deficits in offspring. This study investigated the effects of chronic nicotine exposure during a critical developmental period on the functional expression of nicotinic acetylcholine receptors (nAChRs), glutamatergic synaptic transmission, and auditory processing in the mouse auditory brainstem. We evaluated the functionality of nAChRs at a central synapse and explored the impact of perinatal nicotine exposure (PNE) on synaptic currents and auditory brainstem responses (ABR) in mice. Our findings revealed developmentally regulated changes in nAChR expression in the medial nucleus of the trapezoid body (MNTB) neurons and presynaptic Calyx of Held terminals. PNE was associated with enhanced acetylcholine-evoked postsynaptic currents and compromised glutamatergic neurotransmission, highlighting the critical role of nAChR activity in the early stages of auditory synaptic development. Additionally, PNE resulted in elevated ABR thresholds and diminished peak amplitudes, suggesting significant impairment in central auditory processing without cochlear dysfunction. This study provides novel insights into the synaptic disturbances that contribute to auditory deficits resulting from chronic prenatal nicotine exposure, underlining potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2023

Layer-specific microglia activation drives chronic stress-induced synapse loss

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the mouse medial prefrontal cortex (mPFC). Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (ApoEhigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the ApoEhigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

neuroscience↗