Biology subjects

Mulkey, D. K.

Publications and source records attributed to Mulkey, D. K..

3 recordsLinked to original sources

bioRxiv2022

Clemastine fumarate enhances myelination and promotes functional recovery in a syndromic ASD mouse model of Pitt-Hopkins Syndrome

Pitt-Hopkins syndrome (PTHS) is an autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 gene (TCF4). One pathobiological process caused by Tcf4 mutation is a cell autonomous reduction in oligodendrocytes (OLs) and myelination. In this study, we show that clemastine is effective at restoring myelination defects in a PTHS mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells (OPCs) and normalized OL density. In vivo, two-week intraperitoneal administration of clemastine also normalized OPC and OL density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in uncompacted myelin. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behavior. Together, these results provide preclinical evidence that remyelination therapies may be beneficial in PTHS and potentially other neurodevelopmental disorders characterized by demyelination.

neuroscience↗

bioRxiv2020

Vascular control of the CO2/H+ dependent drive to breathe

Respiratory chemoreceptors regulate breathing in response to changes in tissue CO2/H+. Blood flow is a fundamental determinant of tissue CO2/H+, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO2/H+-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al. 2017). Here, we show in mice that CO2/H+ dilates arterioles in other chemoreceptor regions, thus demonstrating CO2/H+ vascular reactivity in the RTN is unique. We also identify P2Y2 receptors in RTN smooth muscle cells as the substrate responsible for this response. Specifically, pharmacological blockade or genetic deletion of P2Y2 from smooth muscle cells blunted the ventilatory response to CO2, and re-expression of P2Y2 receptors only in RTN smooth muscle cells fully rescued the CO2/H+ chemoreflex. These results identify P2Y2 receptors in RTN smooth muscle cells as requisite determinants of respiratory chemoreception. Significance StatementDisruption of vascular control as occurs in cardiovascular disease leads to compromised chemoreceptor function and unstable breathing. Despite this, virtually nothing is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Here, we identify P2Y2 receptors in RTN vascular smooth muscle cells as a novel vascular element of respiratory chemoreception. Identification of this mechanism may facilitate development of treatments for breathing problems including those associated with cardiovascular disease.

neuroscience↗

bioRxiv2018

Disordered breathing in a mouse model of Dravet syndrome

Dravet syndrome (DS) is a form of epilepsy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Respiratory failure is a leading cause of SUDEP, and DS patients frequently exhibit disordered breathing. Despite this, mechanisms underlying respiratory dysfunction in DS are entirely unknown. We found that mice expressing a recurrent SCN1a missense mutation (A1783V) conditionally in inhibitory neurons (SCN1aA1783V/+; mixed C57B/6 background) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype similar to DS patients including hypoventilation, apnea and a diminished ventilatory response to CO2. At the cellular level in the retrotrapezoid nucleus (RTN), we found inhibitory neurons expressing the SCN1a A1783V variant are less excitable, whereas chemosensitive RTN neurons, which are a key source of the CO2/H+-dependent drive to breathe, are hyper-excitable in slices from SCN1aA1783V/+ mice. These results show loss of SCN1a function can disrupt brainstem respiratory control including at the level of the RTN.

neuroscience↗