Developmental plasticity of GABAergic neurotransmission to brainstem motoneurons

Abstract

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 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.

Developmental Nicotine Exposure Alters Synaptic Input to Hypoglossal Motoneurons and Is Associated with Altered Function of Upper Airway Muscles

“…The key finding is that in P3- to P5-d-old animals, an acute nicotine challenge evoked a marked increase in excitatory synaptic input to XIIMNs in control animals, while the frequency decreased in the DNE pups. Together with previous work showing that nicotine challenge increased GABAergic inhibitory input to XIIMNs (Neff et al, 2003; Jaiswal et al, 2016; Wollman et al, 2018a), these observations suggest that DNE shifts the excitatory-inhibitory balance in XIIMNs toward inhibition in response to a nicotine challenge. This is a deviation from the normal response of neural systems, wherein neuronal spiking activity is maintained within homeostatic limits by careful adjustments in the balance of excitatory and inhibitory synaptic inputs to a neuron or network of neurons (Turrigiano, 2012; Wenner, 2014).…”

“…This is supported by work showing that neuronal development is dependent on the trophic effects of ACh, both in utero and into adolescence, and disruption of nicotinic cholinergic signaling in this developmental window alters brain morphology and function, leading to behavioral abnormalities in both humans and animal models (Slotkin et al, 1987; Navarro et al, 1989; Slotkin, 2004). Additionally, changes in the frequency of inhibitory inputs to XIIMNs are known to occur with DNE (Wollman et al, 2018a,b), and DNE is associated with an increase in the postsynaptic response to muscimol in XIIMNs (Wollman et al, 2018a), consistent with an increase in GABA receptor expression (Jaiswal et al, 2016). Other possibilities include inhibitory effects of nAChR activation, activation of GABAB receptors, which were not blocked, or perhaps nicotine-mediated effects on other neuromodulators that inhibit glutamatergic inputs to XII motoneurons, such as serotonin (Singer et al, 1996).…”

“…For example, XIIMNs from DNE animals have a significantly more complex dendritic arbor than cells from control animals on postnatal days (P)1–P2, but by P3–P4 the arbor is less complex suggesting altered neuronal development over the first week of life (Powell et al, 2016). As for intrinsic properties, XIIMNs from DNE animals are hyperexcitable (Pilarski et al, 2011) and show increased GABAergic inhibition (Jaiswal et al, 2016; Wollman et al, 2018a). We believe that the increase in GABAergic inhibition to nicotine-exposed XIIMNs is consistent with a homeostatic mechanism aimed at mitigating the increased intrinsic excitability.…”

Sex‐specific alterations in GABA receptor‐mediated responses in laterodorsal tegmentum are associated with prenatal exposure to nicotine

“…Similar to other GABAR-focused studies using brain slices (Brodnik, Batra, Oleson, & Espana, 2019;Galeffi, Sah, Pond, George, & Schwartz-Bloom, 2004;Schmidt, Boller, Ozen, & Hall, 2001;Vizuete et al, 2019;Wollman, Levine, & Fregosi, 2018), muscimol was used as the agonist to examine differences in GABA A R functionality associated with PNE. Muscimol is known to exhibit high affinity for synaptically located GABA A R receptors comprised of two α 1-6 , two β 1-4 and one subunit of γ 1-3 δ, ε, ϴ or π, however, it also acts as a partial agonist at the GABA Aρ R subtype (Connolly & Wafford, 2004;Kusama et al, 1993;Woodward, Polenzani, & Miledi, 1993).…”

Challenges and controversies in perinatal physiology

“…Wollman and colleagues also examine perinatal nicotine exposure in rat pups, demonstrating a deleterious impact of perinatal nicotine exposure on GABAergic neurotransmission and the potential impact on the control of homeostatic motor functions such as swallowing and breathing after birth (Wollman et al . ).…”