Developmental nicotine exposure alters neurotransmission and excitability in hypoglossal 1 motor neurons 2 3

34 35 Hypoglossal motor neurons (XII MNs) control muscles of the mammalian tongue, and are 36 rhythmically active during breathing. Acetylcholine (ACh) modulates XII MN activity by 37 promoting the release of glutamate from neurons that express nicotinic ACh receptors (nAChRs). 38 Chronic nicotine exposure alters nAChRs on neurons throughout the brain, including brainstem 39 respiratory neurons. Here we test the hypothesis that developmental nicotine exposure (DNE) 40 reduces excitatory synaptic input to XII MNs. Voltage clamp experiments in rhythmically active 41 medullary slices showed that the frequency of excitatory postsynaptic currents (EPSCs) onto XII 42 MNs from DNE animals is reduced by 61% (DNE = 1.7 ± 0.4 events/sec; control = 4.4 ± 0.6 43 events/sec; p < 0.002). We also examine the intrinsic excitability of XII MNs to test whether 44 cells from DNE animals have altered membrane properties. Current clamp experiments showed 45 XII MNs from DNE animals had higher intrinsic excitability, as evaluated by measuring their 46 response to injected current. DNE cells had high input resistances (DNE = 131.9 ± 13.7 MΩ, 47 control = 78.6 ± 9.7 MΩ, p < 0.008), began firing at lower current levels (DNE = 144 ± 22 pA, 48 control = 351 ± 45 pA, p < 0.003) and exhibited higher frequency-current gain values (DNE = 49 0.087 ± 0.012 Hz/pA, control = 0.050 ± 0.004 Hz/pA, p < 0.02). Taken together, our data 50 show previously unreported effects of DNE on XII MN function, and may also help explain the 51 association between DNE and the incidence of central and obstructive apneas. 52 53