Postsynaptic changes increase the excitability of NTS neurons of mice exposed to hypoxia rather than presynaptic or astrocyte-related mechanisms

Abstract

Cardiovascular and respiratory responses to sustained hypoxia (SH) in rats and mice are different. To understand the contribution of changes in synaptic transmission in nucleus tractus solitarius (NTS) neurons of C57Bl/6J mice to their responses to SH we evaluated the following: (1) the neuronal excitability and excitatory synaptic transmission in the NTS neurons, (2) in what level of the synapses (pre- and postsynaptic) and also(3) to what extent neuron-astrocyte interaction contribute to these changes. Electrophysiological, immunohistochemical and intracellular Ca²⁺ imaging approaches in NTS slices after normoxia (FIO_{2 =} 0.21, 24 h) or SH (FIO_{2 =} 0.10, 24 h) were used. SH increased AMPA and NMDA currents in NTS neurons in response to solitary tract (TS) stimulation, indicating increased glutamatergic excitatory transmission. The number of action potentials after injection of positive current and TS stimulation (10 Hz) was increased by SH. Spontaneous extracellular activity in the NTS also increased, suggesting increased neuronal network activity after SH. The presynaptic mechanisms and the neuron-astrocyte interaction were not affected, but SH increased the amplitude of postsynaptic currents in NTS neurons induced by AMPA and NMDA perfusion. Therefore the enhancement of neuronal excitability and excitatory synaptic transmission in the NTS neurons of mice in response to SH is due to postsynaptic changes rather than changes in presynaptic parameters or in neuron-astrocyte interaction. The findings that the mechanisms underlying the increase in the excitatory synaptic transmission in the NTS of mice and rats are not the same contribute to explain the distinct cardiovascular and respiratory adjustments in mice and rats when exposed to SH. KEY POINTS: Cardiovascular and respiratory responses to sustained hypoxia (SH) in rats and mice are different. The extent to which changes in synaptic transmission in nucleus tractus solitarius (NTS) contribute to these responses is unclear. SH increases excitatory postsynaptic currents in NTS neurons of mice in response to solitary tract (TS) stimulation or to AMPA and NMDA perfusion. SH increases the number of action potentials in NTS neurons in response to injected current and spontaneous extracellular activity evaluated by a multielectrode array. SH did not alter presynaptic parameters, neuron-astrocyte interaction or morphological and electrophysiological properties of astrocytes. Our data show that the overall mechanisms underlying changes in the excitatory synaptic transmission in the NTS neurons of mice in response to SH are different in relation to rats. Although in rats it was documented changes in astrocytic modulation and postsynaptic currents, in mice we are showing that it is restricted to changes in postsynaptic currents.

Keywords: GLT‐1; NTS; excitatory transmission; neuron‐astrocyte interaction; sustained hypoxia.