Abstract
The locus coeruleus (LC)-norepinephrine (NE) system in the brainstem plays a critical role in a variety of behaviors is an important target of pharmacological intervention to several neurological disorders. Although GABA is the major inhibitory neurotransmitter of LC neurons, the modulation of LC neuronal firing activity by local GABAergic interneurons remains poorly understood with respect to their precise location, intrinsic membrane properties and synaptic modulation. Here, we took an optogenetic approach to address these questions. Channelrhodopsin (ChR2) in a tandem with the yellow fluorescent protein (YFP) was expressed in GABAergic neurons under the control of glutamic acid decarboxylase 2 (GAD2) promoter. Immediately dorsomedial to the LC nucleus, a group of GABAergic neurons was observed. They had small soma and were densely packed in a small area, which we named the dorsomedial LC or dmLC nucleus. These GABAergic neurons showed fast firing activity, strong inward rectification and spike frequency adaptation. Lateral inhibition among these GABAergic neurons was observed. Optostimulation of the dmLC area drastically inhibited LC neuronal firing frequency, expanded the spike intervals, and reset their pacemaking activity. Analysis of the light evoked inhibitory postsynaptic currents (IPSCs) indicated that they were monosynaptic. Such light evoked IPSCs were not seen in slices where this group of GABAergic neurons was absent. Thus, an isolated group of GABAergic neurons is demonstrated in the LC area, whose location, somatic morphology and intrinsic membrane properties are clearly distinguishable from adjacent LC neurons. They interact with each and may inhibit LC neurons as well as a part of local neuronal circuitry in the LC.
Highlights
The locus coeruleus (LC) is an isolated nucleus in the pons, deriving >90% norepinephrinergic (NE) neurons in the central nervous system (CNS) [1]
We identified a group of GABAergic neurons in the vicinity of dorsomedial LC, revealed their intrinsic properties, found their synaptic inhibition to each other, and saw some evidence for the inhibition of LC neurons by these GABAergic neurons
To determine the distribution of GABAergic interneurons in the LC region, we expressed channelrhodopsin (ChR2) in a tandem with yellow fluorescent protein (YFP) in GABAergic neurons driven by glutamic acid decarboxylase 2 (GAD2) promoter (Fig 1A)
Summary
The locus coeruleus (LC) is an isolated nucleus in the pons, deriving >90% norepinephrinergic (NE) neurons in the central nervous system (CNS) [1]. Local GABAergic Signaling of Locus Coeruleus of the LC neurons by both intrinsic membrane properties and synaptic inputs are known to affect various behaviors and physiological functions, including attention, anxiety, breathing, arousal state, motor function, etc [2,3,4,5,6]. An increased GABA release is responsible for lower firing frequency of LC neurons in REM sleep, which can be abolished by GABAA receptor antagonists [5, 6]. Certain diseases such as Rett syndrome can cause dramatic defects in both pre- and postsynaptic GABAergic systems contributing to the hyper-excitability of LC neurons [7, 8]
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