Biology subjects

Raymond, L. A.

Publications and source records attributed to Raymond, L. A..

5 recordsLinked to original sources

bioRxiv2024

Effect of chronic upregulation of endocannabinoid signaling in vivo with JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice

Synaptic dysfunction underlies early sensorimotor and cognitive deficits, and precedes neurodegeneration in a variety of disorders, including Alzheimer, Parkinson and Huntington disease (HD). A monogenic inherited disorder, HD manifests with cognitive, motor and mood disorders associated with progressive degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Cortico-basal ganglia-thalamic loops regulate movement selection and motor learning, which are impaired early in HD. Skilled motor learning is mediated in part by plasticity at cortico-striatal synapses, including endocannabinoid-mediated, high-frequency stimulation induced long-term depression (HFS-LTD). Previously, we found impaired HFS-LTD in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation. Here, we tested the effects of JZL184 administered in vivo to YAC128 HD model and wild-type (WT) littermate mice. JZL184, given orally daily over a 3-week period, significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior which was similar for the two genotypes, the treatment improved motor learning on the rotarod task in YAC128 mice to the level observed in WT mice. Moreover, HFS-induced striatal plasticity measured by field potential recording in acute brain slice from YAC128 mice was normalized to WT levels after JZL184 treatment. These results suggest a novel target for mitigating early symptoms of HD, and support the need for clinical trials to test the efficacy of modulating the endocannabinoid system in treatment of HD.

neuroscience↗

bioRxiv2022

Longitudinal assessment of water-reaching reveals altered cortical activity and fine motor coordination defects in a Huntington Disease model

Huntington Disease (HD), caused by dominantly inherited expansions of a CAG repeat results in characteristic motor dysfunction. Although gross motor and balance defects have been extensively characterized in multiple HD mouse models using tasks such as rotarod, beam walking and gait analysis, little is known about forelimb deficits. Here we use a high-throughput alternating reward/non-reward water-reaching task conducted daily over [~]2 months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wildtype (WT) littermate mice, starting at [~]5.5 months of age. Behavioral analysis of the water-reaching task reveals that HD mice, despite learning the water-reaching task as proficiently as WT mice, take longer to learn the alternating event sequence. Although WT mice displayed no significant changes in cortical activity and reaching trajectory throughout the testing period, HD mice exhibited an increase in cortical activity - especially in the secondary motor and retrosplenial cortices - over time, as well as longer and more variable reaching trajectories by [~]7 months of age. HD mice also experienced a progressive reduction in successful performance rates. Tapered beam and rotarod tests before and/or after water-reaching assessment confirmed these early and manifest stages of HD characterized by the absence and presence of failed water-reaching trials, respectively. Reduced DARPP-32 (marker for striatal medium spiny neurons) expression in HD mice further confirmed disease pathology. The water-reaching task can be used to inform HD and potentially other movement disorder onset, therapeutic intervention windows and test drug efficacy. Significance statementThe movement disorder, Huntington Disease (HD), has been extensively studied in preclinical settings using mouse models of disease examining gross motor and balance defects. Little however, is known regarding forelimb deficits and underlying cortical circuit changes. Using a high-throughput alternating reward/non-reward water-reaching task, we characterized early event sequence learning defects in HD mice aged [~]5.5 months. Progressive forelimb movement defects first become apparent at [~]6.5 months of age with corresponding increases in cortical activity associated with reaching observed over time. These forelimb defects revealed in the water-reaching task are coincident with gross motor defects characterized using the tapered beam and rotarod tasks, demonstrating the suitability of the water-reaching task in phenotyping HD motor deficits.

neuroscience↗

bioRxiv2021

Altered cortical processing of sensory input in Huntington disease mouse models

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveal more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

neuroscience↗

bioRxiv2020

Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5s enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

neuroscience↗

bioRxiv2020

Spontaneous Axonal ER Ca2+ Waves Mediate A Shift From Action Potential-Dependent to Independent Glutamate Release in the YAC128 HD-Model

Action potential-independent (miniature) neurotransmission occurs at all chemical synapses, but remains poorly understood, particularly in pathological contexts. Spontaneous release of Ca2+ from the axonal endoplasmic reticulum (ER) is thought to facilitated miniature neurotransmission, and aberrant ER Ca2+ handling is notably implicated in the progression of Huntingtons disease (HD) and other neurodegenerative diseases. Here, we report elevated glutamate-mediated miniature synaptic event frequencies in YAC128 (HD-model) cortical neurons, which pharmacological experiments suggest is mediated by enhanced spontaneous ER Ca2+ release. Calcium imaging using an axon-localized sensor revealed slow action potential (AP)-independent axonal Ca2+ waves, which were more common in YAC128 cortical neurons. Conversely, spontaneous axonal ER Ca2+ release was associated with reduced AP-dependent axonal Ca2+ events and consequent glutamate release. Together, our results suggest spontaneous release of axonal ER Ca2+ stores oppositely regulates activity-dependent and -independent neurotransmitter release in HD, with potential implications for the fidelity and plasticity of cortical excitatory signaling.

neuroscience↗