Biology subjects

Hurley, E. P.

Publications and source records attributed to Hurley, E. P..

3 recordsLinked to original sources

bioRxiv2025

Striatal neuron excitability is regulated by huntingtin in the adult brain

Huntingtons disease (HD) is a hereditary neurodegenerative disease that typically presents during midlife and is characterized by a combination of motor, cognitive and psychiatric symptoms. HD is fatal and arises from a mutation in the huntingtin (HTT) gene, which results in decreased neuronal health followed by brain atrophy, with spiny projection neurons (SPNs) of the striatum being especially vulnerable to degeneration. HTT loss-of-function, caused by haploinsufficiency of the wild type HTT gene (wtHTT), is an important feature of HD pathophysiology that has previously been understudied compared to mutant HTT gain-of-function mechanisms. wtHTT is essential for nervous system development and functions as a scaffolding protein to support many vital cellular functions including axonal transport, autophagy and synaptic plasticity. Here, we examined the consequences of wtHTT deletion in the adult striatum by conditionally inactivating wtHTT in 2-4 month old male and female Httfl/fl mice. wtHTT loss of function in mature SPNs decreased intrinsic neuronal excitability and produced a neuroinflammatory response in these mice, while tissue organization, spine morphology and motor behaviour remained unaffected. Results presented here provide additional evidence that wtHTT is vital for maintaining neuronal health in the adult brain and highlight some potential adverse consequences of non-selective HTT-lowering for the treatment of HD.

neuroscience↗

bioRxiv2022

Atypical NMDA Receptors Limit Synaptic Plasticity in the Adult Ventral Hippocampus

N-methyl-D-aspartate receptors (NMDARs) assemble as functionally diverse heterotetramers. Incorporation of the GluN3A subunit into NMDARs alters conventional NMDAR properties by reducing both magnesium sensitivity and calcium permeability. GluN1 together with GluN3A can also form functional receptors that lack a glutamate binding site and instead serve as excitatory glycine receptors (eGlyRs). GluN3A expression is high in early development but naturally declines to low levels in most brain regions by adulthood. Interestingly, GluN3A expression remains elevated in the CA1 of the adult ventral hippocampus (VH), but not in the dorsal hippocampus (DH). The DH and VH are now well-understood to play very different functional roles, with the DH being primarily involved in cognitive functions and the VH in emotional processing. Why GluN3A persists in the adult VH, and the impact its presence has on glutamatergic neurotransmission in the VH is currently unknown. Here, we show that GluN3A remains elevated both at synaptic and extrasynaptic locations in the adult VH, assembling as GluN1/GluN2/GluN3A NMDARs with reduced magnesium sensitivity, as well as GluN1/GluN3A eGlyRs. By comparing various synaptic properties in the DH and VH of wild-type (WT) and GluN3A knockout (KO) mice, we demonstrate that GluN3A persistence in the VH attenuates glutamate release, limits postsynaptic calcium influx through NMDARs, and reduces the magnitude of NMDAR-dependent long-term potentiation. In comparison, GluN3A KO had relatively little effect on these same properties in the DH. In all, our data demonstrate that GluN3A persistence in the VH represents a key modulator of VH excitability and therefore may play a central role in emotional processing.

neuroscience↗

bioRxiv2022

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer disease

Most research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric: astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.

neuroscience↗