Biology subjects

Levitt, E. S.

Publications and source records attributed to Levitt, E. S..

4 recordsLinked to original sources

bioRxiv2023

Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett Syndrome Mice

Rett Syndrome (RTT) is a severe neurodevelopmental disorder that mainly affects girls and women due to silencing mutations in the X-linked MECP2 gene. One of the most troubling symptoms of RTT is breathing irregularity, including apneas, breath-holds, and hyperventilation. Mice with silencing mutations in Mecp2 exhibit breathing abnormalities similar to human patients and serve as useful models for studying mechanisms underlying breathing problems in RTT. Previous work implicated the pontine, respiratory-controlling Kolliker-Fuse (KF) in the breathing problems in RTT. The goal of this study was to test the hypothesis that inhibitory synaptic transmission is deficient in KF neurons from symptomatic male and female RTT mice. We performed whole-cell voltage-clamp recordings from KF neurons in acute brain slices to examine pharmacologically isolated, spontaneous and electrically evoked inhibitory post-synaptic currents (IPSCs) in RTT mice and age- and sex-matched wild type mice. The frequency of spontaneous IPSCs was reduced in KF neurons from male RTT mice, but not female RTT mice. In addition, electrically evoked IPSCs were less reliable in KF neurons from male RTT mice, but not female RTT mice. KF neurons from male RTT mice were also more excitable and exhibited shorter duration action potentials. Increased excitability of KF neurons from male mice was not explained by changes in axon initial segment length. These findings indicate impaired inhibitory neurotransmission and increased excitability of KF neurons in male, but not female RTT mice, and suggest that sex-dependent mechanisms contribute to breathing problems in RTT. New and NoteworthyKolliker-Fuse (KF) neurons in acute brain slices from male Rett syndrome (RTT) mice receive reduced inhibitory synaptic inputs compared with wild type littermates. In female RTT mice, inhibitory transmission was not different in KF neurons compared with controls. The results from this study show that sex-specific alterations in synaptic transmission occur in the KF of RTT mice. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/560501v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@399b6forg.highwire.dtl.DTLVardef@bc5c3org.highwire.dtl.DTLVardef@e4b98corg.highwire.dtl.DTLVardef@519df7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Glucagon-like peptide-1 receptors in the gustatory cortex influence food intake

The gustatory region of the insular cortex (GC) processes taste information in manners important for taste-guided behaviors, including food intake itself. In addition to oral gustatory stimuli, GC activity is also influenced by physiological states including hunger. The specific cell-types and molecular mechanisms that afford with GC with such influences on food intake are unclear. Glucagon-like peptide 1 (GLP-1) is produced by neurons in the brain whereafter it can act upon GLP-1 receptor-expressing (GLP-1R+) neurons found in several brain regions. In these brain regions, GLP-1R agonism suppresses homeostatic food intake and dampens the hedonic value of food. Here, we report in mice of both sexes that cells within the GC express GLP-1R mRNA and further, by ex vivo brain slice recordings, that GC GLP-1R+ neurons are depolarized by the selective GLP-1R agonist, exendin-4 (Ex-4). Next we found that chemogenetic stimulation of GLP-1R+ neurons, and also pharmacological stimulation of GC-GLP-1Rs themselves, both reduced homeostatic food intake. When maintained on a high-fat diet, obese mice exhibited impaired food intake responses when Ex-4 was administered into the GC. Yet, when obese mice were switched to a low-fat diet, the effect of GC Ex-4 was restored - indicating that GC GLP-1R influences may depend upon palatability of the food. Together, these results provide evidence for a specific cell population in the GC which may hold roles in both homeostatic and hedonic food intake.

neuroscience↗

bioRxiv2022

Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms.

Opioids depress breathing by inhibition of inter-connected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kolliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons is unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the pre-Botzinger complex (preBotC) and rostral ventral respiratory group (rVRG). These medullary projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBotC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. The excitatory preBotC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids. Thus, opioids can synergistically inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms--somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla--all of which could contribute to opioid-induced respiratory depression.

neuroscience↗

bioRxiv2022

Effect of Positive Allosteric Modulation and Orthosteric Agonism of Dopamine D2 Receptors on Respiration in Mouse Models of Rett Syndrome

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2 receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2 receptor positive allosteric modulator, and quinpirole, a dopamine D2 receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2 receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2Bird/+ and Mecp2R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7% CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2R168X/+ and Mecp2Bird/+ mice, while also reducing respiratory rate. These results suggest that D2 receptors do contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of the D2 receptor alone is not sufficient to evoke these effects.

pharmacology and toxicology↗