Gain modulation of respiratory neurons

A possible mechanism underlying adaptive control of the respiratory system is gain modulation of the discharge frequency (F_n) patterns of medullary respiratory neurons mediated by GABA_A receptors. Antagonism of GABA_A receptors with bicuculline results in an F_n pattern that is an amplified replica of the underlying control pattern. The contours of F_n patterns remain proportional to one another. Studies suggest that a tonic GABA_Aergic input constrains the control- and reflexly-induced activities of these neurons to about 35-50% of the discharge rate without this inhibitory input. The pharmacology of this mechanism is unusual in that picrotoxin, a noncompetitive GABA_A receptor antagonist, does not produce gain modulation, but is able to block the silent phase inhibition (e.g. E phase of an I neuron). Alterations in the amplitude of spike afterhyperpolarizations mediated by Ca²⁺ activated K⁺ channels also produces gain modulation. This mechanism modulates exogenously- and endogenously-induced neuronal activities, whereas the bicuculline-sensitive GABAergic mechanism modulates only the respiratory-related activities. Thus, these two forms of gain modulation, acting in cascade manner, may provide robust mechanisms for the optimal control of respiratory, as well as other behavioral functions (e.g. coughing, sneezing, vomiting) mediated by respiratory premotor neurons.