Noradrenergic neuromodulation produces a NMDAR-dependent network state of respiratory rhythmogenesis in the preBotzinger Complex

Abstract

Norepinephrine (NE) is an important mediator of sympathetic activity that influences breathing. At the level of the inspiratory neural network, the preBotzinger complex (preBotC), NE modulation orchestrates changes in neuronal network dynamics that influence the stability of inspiratory rhythmogenesis. While this phenomenon has largely been attributed to NE-modulation of intrinsic excitability of inspiratory preBotC neurons, NE is also capable of modulating synaptic drive. Here, we resolve how NE affects synaptic properties and changes the activity dynamics of interconnected preBotC neurons in rhythmic brainstem slice preparations. Increased network burst amplitude and frequency coincided with enhanced inspiratory drive currents at the single neuron level. This increased drive was blocked by the NMDA receptor (NMDAR) antagonist, APV. Our in silico modeling indicated that synaptic calcium entry via NDMAR is key to maintaining network synchrony during this elevated state of excitability. This was consistent with our multi-electrode array studies revealing that NE-dependent NMDAR activity enhances and preserves synchrony during inspiratory network bursts. This synaptic mechanism may be a critical determinant for shaping inspiratory drive associated with changed neuromodulatory environments. Significance StatementThis study demonstrates a previously undescribed synaptic mechanism by which noradrenergic modulation recruits NMDAR activity and shifts inspiratory network dynamics leading to a stable network state where synchronization is preserved among inspiratory neurons. This may be a critical mechanism preventing ventilatory instability when sympathetic activity is enhanced.