Biology subjects

Maletz, S. N.

Publications and source records attributed to Maletz, S. N..

3 recordsLinked to original sources

bioRxiv2026

Glutamate co-release from catecholaminergic neurons shapes breathing and is inhibited during opioid-induced respiratory depression

Breathing is controlled by a distributed brainstem network that includes multiple catecholaminergic nuclei. The locus coeruleus (LC), the brains primary source of noradrenaline (NA), projects to several respiratory centers, including the Kolliker-Fuse (KF) nucleus in the pons. While LC neurons are predominantly noradrenergic (NAergic), many co-release glutamate, which may contribute to the state-dependent modulation of breathing, particularly during opioid exposure. Here, we examined how opioids affect NAergic and glutamatergic signaling in the LC-KF circuit using optogenetics and whole-cell patch clamp recordings in mouse brain slices. Optogenetic activation of LC terminals evoked glutamatergic excitatory postsynaptic currents (EPSCs) in KF neurons that were presynaptically inhibited by the opioid receptor agonist Met-enkephalin. Additionally, [~]36% of glutamate-responsive KF neurons exhibited postsynaptic opioid inhibition via GIRK currents, while KF neurons receiving excitatory NAergic input showed minimal opioid sensitivity. To assess the behavioral role of glutamate release from all catecholaminergic neurons, we compared breathing in awake VGluT2fl/fl::TH-Cre mice (lacking VGluT2 in tyrosine hydroxylase-positive neurons) to control littermates and TH-Cre hemizygous mice using whole-body plethysmography. The conditional VGluT2 knockout mice exhibited prolonged inspiratory duration, increased tidal volume, and reduced respiratory rate during baseline breathing, with state-dependent differences emerging during hypercapnia. Systemic morphine administration diminished these genotype differences, and machine learning analysis using dynamic time warping confirmed that genotype-specific breathing patterns were distinguishable at baseline, but not after morphine. These findings demonstrate that glutamate co-release from catecholaminergic neurons modulates respiratory patterning in a state-dependent manner and is selectively vulnerable to opioid inhibition.

neuroscience↗

bioRxiv2025

Opposing control of the respiratory brainstem on multiple timescales achieved by transmitter co-release from the locus coeruleus

The locus coeruleus (LC) provides widespread noradrenergic (NAergic) modulation throughout the brain to influence a wide range of functions, including breathing. Although both anatomical and physiological evidence supports the involvement of the LC in both the upstream integration and the downstream modulation of breathing, the circuitry behind the latter is unknown. Here, we show that NAergic LC neurons send projections to the K[o]lliker-Fuse nucleus (KF), a critical site in the control of breathing. Long duration activation of NAergic LC neuron terminals in pontine slices induces persistent inhibitory and excitatory NA currents or increases firing rate in postsynaptic KF neurons. Short stimulation on the other hand leads to the VGluT2-dependent release of glutamate that may be co-released with NA in a monosynaptic circuit. Together these results demonstrate that LC neurons can exert flexible, opposing effects on different timescales via glutamatergic and NAergic signaling onto a key respiratory brainstem nucleus.

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↗