MODULATION OF NEURAL-NETWORK ACTIVITY IN-VITRO BY CYCLOTHIAZIDE, A DRUG THAT BLOCKS DESENSITIZATION OF AMPA RECEPTORS

To determine whether AMPA receptor channel desensitization has a physi ological role in shaping network activity by modulating signal transmi ssion through excitatory circuits, we examined the effects of cyclothi azide (CYT), the most potent known blocker of AMPA receptor desensitiz ation, on the behavior of an endogenously active neural system in vitr o, the brainstem network generating rhythmic respiratory oscillations in neonatal rat medullary slices. Bath application of 100 mu M CYT sig nificantly increased the frequency of endogenously generated rhythm an d increased the amplitude of the circuit output [i.e., discharge of hy poglossal (XII) respiratory motoneurons]. Local application of CYT wit hin the XII motor nucleus produced a concentration-dependent increase (up to 35%) in amplitude of the motoneuron population discharge as wel l as an increase in the peak current (23%) and total charge transfer o f the rhythmic inspiratory synaptic drive (33%) to individual XII moto neurons. CYT also acted postsynaptically to increase the amplitude of spontaneous EPSCs in motoneurons, In addition, CYT produced a profound , long-term augmentation of network frequency and motor output that ma y be secondary to block of desensitization. These results suggest that AMPA receptor desensitization has functionally significant effects on the temporal behavior and output of the rhythmic, respiratory neural network, and, by extrapolation, on other integrative actions of the ma mmalian CNS.