Developmental plasticity of GABAergic neurotransmission to brainstem motoneurons

Critical homeostatic behaviours such as suckling, swallowing and breathing depend on the precise control of tongue muscle activity. Perinatal nicotine exposure has multiple effects on baseline inhibitory GABAergic neurotransmission to hypoglossal motoneurons (XIIMNs), consistent with homeostatic compensations directed at maintaining normal motoneuron output. Developmental nicotine exposure (DNE) alters how GABAergic neurotransmission is modulated by acute activation of nicotinic acetylcholine receptors, which may provide insight into mechanisms by which nicotine exposure alters motor function under conditions that result in increased release of GABA, such as hypoxia, or endogenous acetylcholine, as occurs in the transition from NREM to REM sleep, or in response to exogenous nicotine.

Nicotinic acetylcholine receptor (nAChR) signalling regulates neuronal differentiation and synaptogenesis. Here we test the hypothesis that developmental nicotine exposure (DNE) disrupts the development of GABAergic synaptic transmission to hypoglossal motoneurons (XIIMNs). GABAergic spontaneous and miniature inhibitory postsynaptic currents (sIPSCs/mIPSCs) were recorded from XIIMNs in brainstem slices from control and DNE rat pups of either sex, 1-5 days old, at baseline and following acute stimulation of nAChRs with nicotine. At baseline, sIPSCs were less frequent and smaller in DNE cells (consistent with decreased action potential-mediated GABA release), and mIPSCs were more frequent (consistent with increased vesicular GABA release from presynaptic terminals). Acute nicotine challenge increased sIPSC frequency in both groups, though the increase was greater in DNE cells. Acute nicotine challenge did not change the frequency of mIPSCs in either group, though mIPSC amplitude increased significantly in DNE cells, but not control cells. Stimulation of postsynaptic GABA_A receptors with muscimol caused a significantly greater chloride current in DNE cells than in control cells. The increased quantal release of GABA, coupled with the rise in the strength of postsynaptic inhibition may be homeostatic adjustments to the decreased action-potential-mediated input from GABAergic interneurons. However, this will exaggerate synaptic inhibition under conditions where the release of GABA (e.g. hypoxia) or ACh (sleep-wake transitions) is increased. These findings reveal a mechanism that may explain why DNE is associated with deficits in the ability to respond appropriately to chemosensory stimuli or to changes in neuromodulation secondary to changes in central nervous system state.