GABA-Glycine Cotransmitting Neurons in the Ventrolateral Medulla: Development and Functional Relevance for Breathing

Abstract

Inhibitory neurons crucially contribute to shaping the breathing rhythm in the brain stem. These neurons use GABA or glycine as neurotransmitter; or co-release GABA and glycine. However, the developmental relationship between GABAergic, glycinergic and cotransmitting neurons, and the functional relevance of cotransmitting neurons has remained enigmatic. Transgenic mice expressing fluorescent markers or the split-Cre system in inhibitory neurons were developed to track the three different interneuron phenotypes. During late embryonic development, the majority of inhibitory neurons in the ventrolateral medulla are cotransmitting cells, most of which differentiate into GABAergic and glycinergic neurons around birth and around postnatal day 4, respectively. Functional inactivation of cotransmitting neurons revealed an increase of the number of respiratory pauses, the cycle-by-cycle variability, and the overall variability of breathing. In summary, the majority of cotransmitting neurons differentiate into GABAergic or glycinergic neurons within the first 2 weeks after birth and these neurons contribute to fine-tuning of the breathing pattern.

Inspiratory Off-Switch Mediated by Optogenetic Activation of Inhibitory Neurons in the preBötzinger Complex In Vivo

“…Continuous high frequency optogenetic stimulation of presumptive glycinergic preBötC neurons in the “working heart brainstem preparation”, reduces the respiratory rate; however, stimulation of these glycinergic neurons does not induce robust entrainment of the respiratory rhythm [ 13 ]. The GlyT2-Cre mice used in the present study target—in addition to glycinergic neurons—also at least a subset of GABAergic neurons [ 19 , 20 ], resulting in Chr2 expression in both glycinergic and GABAergic inhibitory neurons. Therefore, the additional optogenetic activation of GABAergic neurons might be critical for phase resetting.…”

Cerebellar and vestibular nuclear synapses in the inferior olive have distinct release kinetics and neurotransmitters

“…VIAAT is nonspecific, and the relative concentrations of glycine and GABA in a vesicle is regulated by the cytosolic levels of GABA and glycine. Corelease of glycine and GABA also occurs at other synapses ( Dufour et al, 2010 ; Hirrlinger et al, 2019 ; Jonas et al, 1998 ; Keller et al, 2001 ; Medelin et al, 2016 ; Nabekura et al, 2004 ; Polter et al, 2018 ; Rahman et al, 2013 ; Rajalu et al, 2009 ; Russier et al, 2002 ; Wu et al, 2002 ). For VN to IO synapses, and other synapses that corelease GABA and glycine, the contribution of GABA and glycine to inhibition could be regulated by the contents of vesicles or by the composition of postsynaptic glycine and GABA receptors.…”

Muscarinic Modulation of Morphologically Identified Glycinergic Neurons in the Mouse PreBötzinger Complex

“…Glycinergic neurons are estimated to constitute about 20-55% of all preBötC neurons, with less than half of them being coupled to inspiration (Manzke et al, 2010;Morgado-Valle et al, 2010). A substantial subpopulation of inhibitory neurons expresses both glycine and GABA (Koizumi et al, 2013;Rahman et al, 2013;Hirrlinger et al, 2019). The majority of preBötC glycinergic neurons recorded in this study in mouse brainstem slices fired spontaneously with regular repetitive APs under our experimental conditions, where excitatory synaptic transmission was left intact and GABAergic inhibition was blocked.…”