Pre- and postsynaptic modulations of hypoglossal motoneurons by α-adrenoceptor activation in wild-type and Mecp2^−/Y mice

Abstract

Hypoglossal motoneurons (HNs) control tongue movement and play a role in maintenance of upper airway patency. Defects in these neurons may contribute to the development of sleep apnea and other cranial motor disorders including Rett syndrome (RTT). HNs are modulated by norepinephrine (NE) through α-adrenoceptors. Although postsynaptic mechanisms are known to play a role in this effect, how NE modulates the synaptic transmissions of HNs remains poorly understood. More importantly, the NE system is defective in RTT, while how the defect affects HNs is unknown. Believing that information of NE modulation of HNs may help the understanding of RTT and the design of new therapeutical interventions to motor defects in the disease, we performed these studies in which glycinergic inhibitory postsynaptic currents and intrinsic membrane properties were examined in wild-type and Mecp2(-/Y) mice, a mouse of model of RTT. We found that activation of α1-adrenoceptor facilitated glycinergic synaptic transmission and excited HNs. These effects were mediated by both pre- and postsynaptic mechanisms. The latter effect involved an inhibition of barium-sensitive G protein-dependent K(+) currents. The pre- and postsynaptic modulations of the HNs by α1-adrenoceptors were not only retained in Mecp2-null mice but also markedly enhanced, which appears to be a compensatory mechanism for the deficiencies in NE and GABAergic synaptic transmission. The existence of the endogenous compensatory mechanism is an encouraging finding, as it may allow therapeutical modalities to alleviate motoneuronal defects in RTT.

Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model

“…Experimental evidence indicates that the Mecp2 disruption causes an increase in neuronal activity or excitability in the brainstem, hippocampus, and neocortex (Stettner et al, ; Zhang et al, , ; Katz et al, ; Taneja et al, ; Calfa et al, , ; Gantz et al, ; Kron et al, ; Jin et al, ,; Ramirez et al, ). This is associated with decreased GABA inhibition, increased glutamate concentration and defects in intrinsic membrane properties, although defects in NMDA, AMPA, NE, serotonin, dopamine, and acetylcholine neurotransmitter/neuromodulator systems have also been found, some of which have excitatory effects (Katz et al, ; Ramirez et al, ).…”

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons

“…Several groups of respiratory neurons and motoneurons are modulated by NE because NE augments cellular excitability via ␣ adrenoceptors (62,63). This NEergic modulation relies on firing activity and NE biosynthesis in LC neurons.…”

An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons

“…In a previous study, we showed the postsynaptic modulation of hypoglossal motoneurons (HNs) by NE (Jin et al, ). These neurons may remain to be modulated in the medullary slice preparation because the NEergic neurons are found in area postrema (Viemari, et al, ).…”

“…One group of brainstem neurons targeted by NE modulation is the HNs. NE augments their firing activity by pre‐ and postsynaptic mechanisms (Jin et al, ). Such an NEergic modulation is defective in Mecp2 null mice, suggesting that HNs are ideal for testing NE modulation in our TH‐ChR‐ Mecp2 −/Y mice.…”