Biology subjects

Henderson, B. J.

Publications and source records attributed to Henderson, B. J..

3 recordsLinked to original sources

bioRxiv2025

Adolescent Alcohol Exposure Disrupts Astrocyte-Synaptic Structural And Functional Coupling In The Male Dorsal Hippocampus

Adolescence is a window of heightened vulnerability to the neurotoxic effects of binge ethanol exposure. Adolescent intermittent ethanol (AIE) exposure has been shown to induce long-lasting cognitive and behavioral impairments in patients and rodent models that increase the risk of developing alcohol use disorder (AUD). Our previous work shows that these behavioral deficits coincide with persistent astrocyte dysfunction. Here, we aim to understand how astrocyte-synaptic structural and functional crosstalk are disrupted following AIE to provide better mechanistic understanding of why behavioral impairments persist into adulthood. Male Sprague-Dawley rats received AIE, a variety of adeno-associated viruses encoding astrocyte-specific sensors, and fiber implantation in the dorsal hippocampal (dHipp) for in vivo photometry. A subset of rats received hM3D(Gq) to chemogenetically activate astrocytes. Following AIE and a forced abstinence period that allowed growth into adulthood, rats underwent assessment in the contextual fear conditioning (CFC) task with simultaneous fiber photometry recordings. By combining immunohistochemistry (IHC), Stimulated Emission Depletion (STED) microscopy, fiber photometry, chemogenetics, and slice physiology, we show that AIE induces structural and functional decoupling of astrocytes from synapses and astrocyte dysregulation that persists into adulthood. Remarkably, stimulating astrocytic calcium signaling via chemogenetic activation partially attenuates heightened fear responding and increases gliotransmitter availability. These findings highlight a critical role for astrocyte-synaptic crosstalk in regulating fear learning and underscore the untapped therapeutic potential of targeting astrocytes to improve behavioral outcomes following substance use.

neuroscience↗

bioRxiv2022

Hsp47 Promotes Biogenesis of Multi-subunit Neuroreceptors in the Endoplasmic Reticulum

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurodegenerative, neurological, and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is not well understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric type A (GABAA) receptors. Here, we show that Hsp47 enhances neuronal GABAA receptor functional surface expression, acting after Binding immunoglobulin Protein (BiP) to preferentially bind the folded conformation of GABAA receptors. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. These Hsp47 properties are also extended to other Cys-loop receptors, including nicotinic acetylcholine receptors. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 also plays a critical and general role in the maturation of multi-subunit neuroreceptors. HighlightsO_LIHsp47 positively regulates the functional surface expression of endogenous GABAA receptors. C_LIO_LIHsp47 acts after BiP and preferentially binds the folded conformation of GABAA receptors. C_LIO_LIHsp47 promotes the subunit-subunit assembly of GABAA receptors. C_LIO_LIHsp47 plays a critical and general role in the maturation of multi-subunit neuroreceptors. C_LI

cell biology↗

bioRxiv2021

Astrocyte-derived thrombospondin induces cortical synaptogenesis in a sex-specific manner.

The regulation of synaptic connectivity in the brain is vital to proper functioning and development of the central nervous system (CNS). Formation of neural networks in the CNS has been shown to be heavily influenced by astrocytes, which secrete factors, including thrombospondin (TSP) family proteins, that promote synaptogenesis. However, whether this process is different between males and females has not been thoroughly investigated. In this study, we found that cortical neurons purified from newborn male rats showed a significantly more robust synaptogenic response compared to female-derived cells when exposed to factors secreted from astrocytes. This difference was driven largely by the neuronal response to TSP2, which increased synapses in male neurons while showing no effect on female neurons. Blockade of endogenous 17{beta}-estradiol production with letrozole normalized the TSP response between male and female cells, indicating a level of regulation by estrogen signaling. Our results suggest that TSP-induced synaptogenesis is critical for the development of male but not female cortical synapses, contributing to sex differences in astrocyte-mediated synaptic connectivity.

neuroscience↗