308-310 Neurons in both nuclei have inherent

rhythmic GDC-0973 price potential due in part to low-threshold T-type Ca2+ currents that predispose the cells to rebound excitation; such conductances are known to underlie many forms of pacemaker activity.311-314 The predilection for oscillatory interactions between GPe and STN is normally restrained by powerful local GABAergic feedback that desynchronizes the output of neighboring neurons Inhibitors,research,lifescience,medical in GPe.315,316 These and other connectional and biophysical properties of the GPe-STN network have been incorporated into dynamic computational models that successfully reproduce and illuminate much of the pathophysiology of oscillatory activity observed in PD and MPTP-induced parkinsonism.317 Such models show, for example, that increased striatal activity along the indirect pathway can lead to oscillator}’ activity in the GPe-STN network by two concurrent, mechanisms. Increased GABAergic striatal Inhibitors,research,lifescience,medical input to GPe will reduce the latter’s tonic GABAergic suppression of STN activity, allowing the oscillatory potential of the reciprocal antagonism between GPe and STN to be expressed.317 Accompanying

the increased release of GABA at striatoGPe synapses will be a Inhibitors,research,lifescience,medical corresponding increase in the release of colocalized enkephalin.256,318 Local diffusion of enkephalin Inhibitors,research,lifescience,medical within GPe will lead to presynaptic suppression of GABA release not only at the striatoGPe terminals themselves, but also at the sites of local GABAergic feedback from neighboring GPe neurons318; the net effect,

of this reduced lateral inhibition will be enhanced synchronization among the GPe-STN projection cells.317 The recent incorporation Inhibitors,research,lifescience,medical of dynamic features of neuronal interactions into the ever more complex functional models of basal ganglia, circuitry317 permits us now to account, Adenylyl cyclase for most, if not all of the observed motor dysfunction in PD. With the demonstrable linkage between motor deficits and abnormal oscillatory activity, and growing understanding of how the oscillatory activity arises naturally under conditions of striatal DA depletion, it seems we are approaching the point of having a reasonably comprehensive and testable theory of the pathophysiology of PD. Much of the testing can and should be carried out in experimental studies of basal ganglia-thalamocortical circuitry in MPTP-induced parkinsonism. Some will likely be incidental to attempts to refine and improve current symptomatic therapies, both pharmacological and neurosurgical, in patients with PD.