Rett Syndrome (RTT) is a neurodevelopmental disorder affecting 1 out of 10,000 females worldwide. Mutations of the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2) accounts for >90% of RTT cases. People with RTT and mice with Mecp2 disruption show autonomic dysfunction, especially life-threatening breathing disorders, which involves defects in brainstem neurons for breathing controls, including neurons in the locus coeruleus (LC). Accumulating evidence obtained from Mecp2−/Y mice suggests that imbalanced excitation/inhibition or the impaired synaptic communications in central neurons plays a major role. LC neurons in Mecp2−/Ymice are hyperexcited, attributable to the deficiency in GABA synaptic inhibition. Several previous studies indicate that augmenting synaptic GABA receptors (GABARs) leads to a relief of RTT-like symptoms in mice. The extrasynaptic GABARs located outside synaptic cleft, which have the capability to produce sustained inhibition, and may be a potential therapeutic target for the rebalance of excitation/inhibition in RTT. In contrast to the rich information of the synaptic GABARs in RTT research, however, whether Mecp2 gene disruption affects the extrasynaptic GABARs remains unclear. In this study, we show evidence that the extrasynaptic GABAR mediated tonic inhibition of LC neurons was enhanced in Mecp2−/Ymice, which seems attributable to the augmented δ subunit expression. Low-dose THIP exposure, an agonist specific to δ subunit containing extrasynaptic GABARs, extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of Mecp2−/Ymice. Such beneficial effects were associated with stabilization of brainstem neuronal hyperexcitability, including neurons in the LC and the mesencephalic trigeminal V nucleus (Me5), and improvement of norepinephrine (NE) biosynthesis. Such phenomena were found in symptomatic Mecp2+/− (sMecp2+/−) female mice model as well, in which the THIP exposure alleviated the hyperexcitability of both LC and Me5 neurons to a similar level as their counterparts in Mecp2−/Y mice, and improved breathing function. In identified LC neurons of sMecp2+/− mice, the hyperexcitability appeared to be determined by both MeCP2 expression and their environmental cues. In conclusion, intervention to extrasynaptic GABAAR by chronic treatment with THIP might be a therapeutic approach to RTT-like symptoms in both Mecp2−/Y and Mecp2+/− mice models and perhaps in people with RTT as well.

A recent model of Parkinson’s disease (PD) suggests that the neuropathological, behavioural and cognitive symptoms progress in stages. There is substantial evidence for a prodromal stage of PD, during which time pre-motor symptoms develop. Rapid eye movement (REM) sleep behaviour disorder (RBD) is a risk factor for developing PD and may be part of the pre-motor stage. In both disorders, neuropathological α-synuclein aggregates are thought to be a direct cause of the resulting symptoms. One model has shown that in rats, proteasome inhibition produced by systemic exposure to environmental toxins results in α-synuclein pathology and motor behaviour dysfunction that mimics the progression of PD in humans. The present study examined the hypothesis that the systemic proteasome inhibition model would produce pre-Parkinsonian RBD-like pathology in rats. It was expected that sleep disturbances would be seen prior to behavioural disturbances in rats treated systemically with PSI (a proteasome inhibitor). Following baseline sleep recording and training on the inclined beam-traverse task, rats were injected with PSI (a proteasome inhibitor) or ethanol (control), 6 times over 2 wk. Sleep recording over 8 wk and behavioural testing over 16 wk provided no evidence of sleep disturbances or motor dysfunction. Post-mortem immunohistochemical analyses of brain tissue provided no evidence of PSI-associated α-synuclein aggregates in the locus coeruleus, subcoeruleus (dorsal part), or substantia nigra (areas involved in RBD and/or PD). These results did not provide support for RBD as a prodromal phase of PD within the systemic proteasome inhibitor-based model and add to a growing body of research reporting inconsistent findings using this model. We suggest that systemic PSI exposure in rats does not produce a viable model of RBD or PD. Whether RBD is an early symptom in the progression of PD remains to be established. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-04-28 12:04:50.613

No description available.

Made available in DSpace on 2016-06-02T19:22:55Z (GMT). No. of bitstreams: 1 4102.pdf: 1499777 bytes, checksum: 83d49633865ad84ab741b0091f168280 (MD5) Previous issue date: 2011-12-14 / Universidade Federal de Minas Gerais / Locus coeruleus (LC) is considered as a chemosensitive region to CO2/pH in mammals and amphibians, mainly its noradrenergic neurons. The LC purinergic neuromodulation is of particular interest since adenosine 5′-triphosphate (ATP) acts as a neuromodulator in many brainstem areas involved in cardiovascular and respiratory regulation, which includes Locus coeruleus (LC). ATP acting on LC P2 receptors influences the release of noradrenaline (NE) and the LC noradrenergic neurons are involved in the CO2-drive to breathing. Thus, the goal of the present study was to investigate the role of purinergic neuromodulation in the LC in the ventilatory, thermal and cardiovascular responses during normocapnia and hypercapnia in Wistar male unanesthetized rats. We assessed the purinergic modulation of cardiorespiratory and thermal responses by microinjecting ATP P2X receptor agonist (α,β-MeATP, 0.5 nmoL/40 nL and 1 nmoL/40 nL) and P2 receptor non selective antagonists (PPADS 0.5 nmoL/40 nL and 1 nmoL/40 nL; suramin, 1 nmoL/40 nL) into the LC. Pulmonary ventilation (VE, plethysmography), mean arterial pressure (MAP), heart rate (HR) and body core temperature (Tb, dataloggers) were measured before and after unilateral microinjection (40 nL) of α,β-MeATP, PPADS, suramin or 0.9% saline (vehicle) into the LC during 60 min normocapnia or 30 min period of 7% CO2 exposure followed by 30 min of normocapnia. Under normocapnic conditions, α,β-MeATP did not affect any parameter, whereas PPADS decreased respiratory frequency (f), increased MAP and HR and suramin increased Tb, MAP and HR and did not change ventilation. Hypercapnia induced an increase in ventilation, a fall in HR and did not change Tb in all groups. During hypercapnia, α,β-MeATP produced a further increase in ventilation and did not cause changes in cardiovascular and thermal parameters, PPADS caused an increase in MAP, did not alter ventilation and Tb and suramin elicited increases in ventilation, MAP and bradycardia and did not change Tb. Thus, our data suggest that purinergic neuromodulation in the LC plays an important role in the cardiorespiratory control during hypercapnia and modulates cardiorrespiratory and thermal control during normocapnic conditions in unanesthetized animals. / O LC é considerado uma região quimiossensível a CO2/pH em mamíferos e anfíbios, especificamente os neurônios noradrenérgicos. A neuromodulação purinérgica no LC desperta um interesse particular uma vez que a adenosina 5 -trifosfato (ATP) atua como neuromodulador em várias áreas do tronco encefálico envolvidas na regulação cardiorrespiratória, incluindo o LC e sua atuação em receptores P2 influencia a liberação de noradrenalina (NE) dos neurônios do LC. Portanto, o objetivo do presente estudo foi investigar a participação da neuromodulação purinérgica no LC nas respostas ventilatória, térmica e cardiovascular durante normocapnia e hipercapnia em ratos Wistar não anestesiados. A possível modulação do ATP nessas respostas foi realizada por meio da microinjeção do agonista de receptor P2X (α,β-MeATP, 0.5 nmol/40 nL e 1 nmol/40 nL) e dos antagonistas não seletivos de receptor P2 (PPADS 0.5 nmol/40 nL e 1 nmol/40 nL; suramin, 1nmol/40nL) no LC. Foram feitas medidas de ventilação pulmonar ( VE, pletismografia), temperatura corporal (TC) pressão arterial média (PAM) e frequência cardíaca (FC) antes da microinjeção unilateral de α,β--MeATP, PPADS, suramin ou salina (veículo, 40nL) no LC em condições basais, e após microinjeção durante 60 min de normocapnia ou 30 min de exposição a 7% CO2, seguido de 30 min de normocapnia. Em condições normocápnicas, a microinjeção de α,β-MeATP não afetou nenhuma das variáveis analisadas, enquanto que o PPADS promoveu uma redução da freqüência respiratória (fR), aumento da PAM e FC, e o suramin aumentou a TC, PAM e FC sem causar alterações na ventilação. A hipercapnia promoveu aumento da ventilação, uma redução na FC e não alterou a TC em todos os grupos. Durante hipercapnia, α,β-MeATP promoveu aumento da hiperpnéia sem causar alterações nas variáveis cardiovasculares e na temperatura, PPADS promoveu aumento da PAM sem alterar as variáveis respiratórias e a temperatura corporal e o suramin promoveu aumento da hiperventilação, aumento na PAM e bradicardia sem alterar a temperatura corporal. Portanto, nossos dados sugerem que a neuromodulação purinérgica no LC participa do controle cardiorrespiratório durante normocapnia e hipercapnia e modula a termorregulação em condições normocápnicas em animais não anestesiados.