GABAergic synaptic inputs of locus coeruleus neurons in wild-type and Mecp2-null mice

Abstract

Rett syndrome is an autism spectrum disorder resulting from defects in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Deficiency of the Mecp2 gene causes abnormalities in several systems in the brain, especially the norepinephrinergic and GABAergic systems. The norepinephrinergic neurons in the locus coeruleus (LC) modulate a variety of neurons and play an important role in multiple functions in the central nervous system. In Mecp2(-/Y) mice, defects in the intrinsic membrane properties of LC neurons have been identified, while how their synaptic inputs are affected remains unclear. Therefore, we performed these brain slice studies to demonstrate how LC neurons are regulated by GABAergic inputs and how such synaptic inputs are affected by Mecp2 knockout. In whole cell current clamp, the firing activity of LC neurons was strongly inhibited by the GABAA receptor agonist muscimol, accompanied by hyperpolarization and a decrease in input resistance. Such a postsynaptic inhibition was significantly reduced (by ~30%) in Mecp2(-/Y) mice. Post- and presynaptic GABABergic inputs were found in LC neurons, which were likely mediated by the G protein-coupled, Ba(2+)-sensitive K(+) channels. The postsynaptic GABABergic inhibition was deficient by ~50% in Mecp2 knockout mice. Although the presynaptic GABABergic modulation appeared normal, both frequency and amplitude of the GABAAergic mIPSCs were drastically decreased (by 30-40%) in Mecp2-null mice. These results suggest that the Mecp2 disruption causes defects in both post- and presynaptic GABAergic systems in LC neurons, impairing GABAAergic and GABABergic postsynaptic inhibition and decreasing the GABA release from presynaptic terminals.

A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice

“…However, these mice also display decreased phasic GABA A receptor activity due to the diminished frequency of spontaneously released GABA from presynaptic inhibitory terminals (Jensen et al, 2003). Thus, the enhanced activity of GABA B receptors we show here with GS-39783, and the decreased levels of phasic inhibition shown previously at MeCP2-deficient synapses (Chao et al, 2010;Jin et al, 2013), can co-exist in systems with decreased GAT-1 transporter activity. It is also noteworthy that many of the behavioral deficits and general phenotypes of GAT-1 knockout mice (Chiu et al, 2005;Liu et al, 2007) display considerable overlap with those of MeCP2-deficient mice (Katz et al, 2012).…”

“…Indeed, phasic GABA signaling through synaptic GABA A receptors is altered in different regions of the MeCP2-deficient brain (Chao et al, 2010;Zhang et al, 2010;Jin et al, 2013), and has been proposed to be an underlying cause of local synaptic hyper-excitability (Chao et al, 2010). Although heightened extra-synaptic GABAergic tone may initially seem inconsistent with attenuated phasic GABAergic synaptic activity, the two are not mutually exclusive.…”

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

“…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). Consistent with these observations, defects in the GABA A receptor (GABA A R) system are also found in other brain regions (11)(12)(13)(14).…”

“…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).…”

“…Indeed, several recent studies have shown that the breathing disorders of Mecp2-null mice can be alleviated by augmenting GABA synaptic inhibition (20,21). In contrast to the rich information of the synaptic GABA A Rs in RTT research (10,11,13,(22)(23)(24)(25), how the extrasynaptic GABA A Rs are affected by Mecp2 disruption remains unknown. The capability of these extrasynaptic GABA A Rs to reduce neuronal excitability without interrupting synaptic transmission suggests that these receptors may allow an alternative therapeutic intervention to RTT.…”