Yasin B. Seven

Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation

Although adenosine 2A (A2A) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing these receptors. Cervical spinal adenosine 2A (A2A) receptor activation elicits a prolonged facilitation in phrenic nerve activity, which was nearly abolished following intrapleural A2A receptor siRNA injections. A2A receptor siRNA injections selectively knocked down A2A receptors in cholera toxin B‐subunit‐identified phrenic motor neurons, sparing cervical non‐phrenic motor neurons. Collectively, our results support the hypothesis that phrenic motor neurons express the A2A receptors relevant to A2A receptor‐induced phrenic motor facilitation. Upregulation of A2A receptor expression in the phrenic motor neurons per se may potentially be a useful approach to increase phrenic motor neuron excitability in conditions such as spinal cord injury.

Partial loss of ATP13A2 causes selective gliosis independent of robust lipofuscinosis

&NA; Loss‐of‐function mutations in ATP13A2 are associated with three neurodegenerative diseases: a rare form of Parkinsons disease termed Kufor‐Rakeb syndrome (KRS), a lysosomal storage disorder termed neuronal ceroid lipofuscinosis (NCL), and a form of hereditary spastic paraplegia (HSP). Furthermore, recent data suggests that heterozygous carriers of mutations in ATP13A2 may confer risk for the development of Parkinsons disease, similar to the association of mutations in glucocerebrosidase (GBA) with both Parkinsons disease and Gauchers disease, a lysosomal storage disorder. Mutations in ATP13A2 are generally thought to be loss of function; however, the lack of human autopsy tissue has prevented the field from determining the pathological consequences of losing functional ATP13A2. We and others have previously neuropathologically characterized mice completely lacking murine Atp13a2, demonstrating the presence of lipofuscinosis within the brain – a key feature of NCL, one of the diseases to which ATP13A2 mutations have been linked. To determine if loss of one functional Atp13a2 allele can serve as a risk factor for disease, we have now assessed heterozygous Atp13a2 knockout mice for key features of NCL. In this report, we demonstrate that loss of one functional Atp13a2 allele leads to both microgliosis and astrocytosis in multiple brain regions compared to age‐matched controls; however, levels of lipofuscin were only modestly elevated in the cortex of heterozygous Atp13a2 knockout mice over controls. This data suggests the possibility that partial loss of ATP13A2 causes inflammatory changes within the brain which appear to be independent of robust lipofuscinosis. This study suggests that heterozygous loss‐of‐function mutations in ATP13A2 are likely harmful and indicates that glial involvement in the disease process may be an early event that positions the CNS for subsequent disease development. HighlightsPathological consequences of complete and partial loss of murine Atp13a2 are reported.Loss of two functional Atp13a2 alleles yields widespread lipofuscinosis and gliosis.Loss of one functional Atp13a2 allele also leads to gliosis in multiple brain regions, independent of lipofuscinosis.

Compensatory plasticity in diaphragm and intercostal muscle utilization in a rat model of ALS

ABSTRACT In SOD1G93A transgenic rat model of ALS, breathing capacity is preserved until late in disease progression despite profound respiratory motor neuron (MN) cell death. To explore mechanisms preserving breathing capacity, we assessed inspiratory EMG activity in diaphragm and external intercostal T2 (EIC2) and T5 (EIC5) muscles in anesthetized SOD1G93A rats at disease end‐stage (20% decrease in body mass). We hypothesized that despite significant phrenic motor neuron loss and decreased phrenic nerve activity, diaphragm electrical activity and trans‐diaphragmatic pressure (Pdi) are maintained to sustain ventilation. We alternatively hypothesized that EIC activity is enhanced, compensating for impaired diaphragm function. Diaphragm, EIC2 and EIC5 muscle EMGs and Pdi were measured in urethane‐anesthetized, spontaneously breathing female SOD1G93A rats versus wild‐type littermates during normoxia (arterial PO2 ˜ 90 mm Hg, PCO2 ˜ 45 mm Hg), maximal chemoreceptor stimulation (MCS: 10.5% O2/7% CO2), spontaneous augmented breaths and sustained tracheal occlusion. Phrenic MNs were counted in C3–5; T2 and T5 ventrolateral MNs were counted. In end‐stage SOD1G93A rats, 29% of phrenic MNs survived (vs. wild‐type), yet integrated diaphragm EMG amplitude was normal. Nevertheless, maximal Pdi decreased ˜ 30% vs. wild type (p < 0.01) and increased esophageal to gastric pressure ratio (p < 0.05), consistent with persistent diaphragm weakness. Despite major T2 and T5 MN death, integrated EIC2 (100% greater than wild type) and EIC5 (300%) EMG amplitudes were increased in mutant rats during normoxia (p < 0.01), possibly compensating for decreased Pdi. Thus, despite significant phrenic MN loss, diaphragm EMG activity is maintained; in contrast, Pdi was not, suggesting diaphragm dysfunction. Presumably, increased EIC EMG activity compensated for persistent diaphragm weakness. These adjustments contribute to remarkable preservation of breathing ability despite major respiratory motor neuron death and diaphragm dysfunction. HIGHLIGHTSSOD1G93A rats preserve ventilatory capacity despite significant phrenic motor neuron loss and reduced phrenic nerve activity.Diaphragm EMG is maintained suggesting amplified transmission of phrenic nerve activity to the diaphragm activity.Decreased transdiaphragmatic pressure and diaphragm muscle contribution to breathing suggests diaphragm dysfunction.Diaphragm dysfunction is compensated by enhanced external intercostal activity.Compensatory plasticity mechanisms preserve breathing despite respiratory motor neuron loss and diaphragm dysfunction.