Putting the theory into 'burstlet theory' with a biophysical model of burstlets and bursts in the respiratory preBotzinger complex

Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBotzinger complex (preBotC). In in vitro slice preparations containing the preBotC, extracellular potassium must be elevated above physiological levels (to 7-9 mM) to observe regular rhythmic respiratory motor output in the hypoglossal nerve to which the preBotC projects. Reexamination of how extracellular K+ affects preBotC neuronal activity has revealed that low-amplitude oscillations persist at physiological levels. These oscillatory events are subthreshold from the standpoint of transmission to motor output and are dubbed burstlets. Burstlets arise from synchronized neural activity in a rhythmogenic neuronal subpopulation within the preBotC that in some instances may fail to recruit the larger network events, or bursts, required to generate motor output. The fraction of subthreshold preBotC oscillatory events (burstlet fraction) decreases sigmoidally with increasing extracellular potassium. These observations underlie the burstlet theory of respiratory rhythm generation. Experimental and computational studies have suggested that recruitment of the non-rhythmogenic component of the preBotC population requires intracellular Ca2+ dynamics and activation of a calcium-activated nonselective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca2+ influx as well as Ca2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated nonselective cationic current can reproduce and offer an explanation for many of the key properties associated with the burstlet theory of respiratory rhythm generation. Altogether, our modeling work provides a mechanistic basis that can unify a wide range of experimental findings on rhythm generation and motor output recruitment in the preBotC.