Intrinsic membrane properties of locus coeruleus neurons in Mecp2-null mice

Abstract

Rett syndrome caused by mutations in methyl-CpG-binding protein 2 (Mecp2) gene shows abnormalities in autonomic functions in which brain stem norepinephrinergic systems play an important role. Here we present systematic comparisons of intrinsic membrane properties of locus coeruleus (LC) neurons between Mecp2(-/Y) and wild-type (WT) mice. Whole cell current clamp was performed in brain slices of 3- to 4-wk-old mice. Mecp2(-/Y) neurons showed stronger inward rectification and had shorter time constant than WT cells. The former was likely due to overexpression of inward rectifier K(+) (K(ir))4.1 channel, and the latter was attributable to the smaller cell surface area. The action potential duration was prolonged in Mecp2(-/Y) cells with an extended rise time. This was associated with a significant reduction in the voltage-activated Na(+) current density. After action potentials, >60% Mecp2(-/Y) neurons displayed fast and medium afterhyperpolarizations (fAHP and mAHP), while nearly 90% WT neurons showed only mAHP. The mAHP amplitude was smaller in Mecp2(-/Y) neurons. The firing frequency was higher in neurons with mAHP, and the frequency variation was greater in cells with both fAHP and mAHP in Mecp2(-/Y) mice. Small but significant differences in spike frequency adaptation and delayed excitation were found in Mecp2(-/Y) neurons. These results indicate that there are several electrophysiological abnormalities in LC neurons of Mecp2(-/Y) mice, which may contribute to the dysfunction of the norepinephrine system in Rett syndrome.

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

“…Mecp2 disruption in mice also causes hyperexcitability in LC neurons and impaired metabolic activity, which is attributable to the defects in neuronal intrinsic membrane properties and insufficient GABA inputs (4,9,33). Consistent with these findings, treatment with GABA or diazepam rebalances the hyperexcitability of expiratory neurons and improves the breathing activity in Mecp2-null mice (20,21).…”

“…Brain Slice Preparation-Brain slices were prepared as described previously (4,26). In brief, a mouse was decapitated after deep anesthesia with inhalation of saturated isoflurane.…”

“…The defect manifests itself as reduced expression of NE synthetic enzymes, hyperexcitability, and impaired CO 2 chemosensitivity (4 -9). The hyperexcitability of LC neurons is attributable to the intrinsic membrane properties of the cells and a decrease in synaptic inhibition mediated by GABA (4,10). Both GABA A and GABA B receptormediated postsynaptic inhibition are reduced, and the GABA release from presynaptic terminals is significantly low (10).…”

“…In Mecp2-null mice, several groups of neurons, including LC neurons, are hyperexcitable (4,20,23,33), which appears to contribute to the breathing disorders in Mecp2-null mice. To test whether activation of the extrasynaptic GABA A Rs can alleviate the breathing abnormalities, we studied breathing activity using plethysmography in conscious Mecp2-null mice.…”

Involvement of TRP channels in the CO2 chemosensitivity of locus coeruleus neurons

“…All animal procedures were conducted in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were approved by the Georgia State University Institutional Animal Care and Use Committee. Brain slices were prepared as described previously (Zhang et al 2010a). In brief, C57BL/6 mice at age 2-3 wk were decapitated after anesthetized by inhalation of saturated isoflurane.…”