PRE AND POST SYNAPTIC SEROTONINERGIC EXCITATION OF GLOBUS PALLIDUS NEURONS Running title: 5-HT excite pallidal neurons

The basal ganglia (BG) play a critical role in the pathogenesis and pathophysiology of Parkinson’s disease (PD). Recent studies indicate that serotoninergic systems modulate BG activity, and may be implicated in the pathophysiology and treatment of PD. The globus pallidus (GP), the rodent homologue of the primate GPe, is the main central nucleus of the basal ganglia, affecting the striatum, the subthalamic nucleus (STN) and BG output structures. We therefore studied the effect of serotonin (5-HT) and specific 5-HT agonist and antagonist on GP neurons from rat brain slices. Using intra and extra-cellular recording of GP neurons we found that serotonin increases the firing rate of GP neurons. Analyzing the effects of specific 5-HT agonist and antagonist on the firing rate of GP neurons showed that the increase in firing rate is due to the activation of 5-HT1B and 5-HT1A receptors. Intracellular recordings in voltage and current clamp mode revealed that serotonin mediates its effect via pre and post synaptic mechanisms. The pre synaptic effect is mediated by attenuation of GABA release, probably through activation of 5-HT1B receptors. Post synaptically, serotonin activates a hyperpolarization-activated cation channel, probably via 5-HT1A receptors. Furthermore, serotonin decreases the fast synaptic depression characteristic of the striatal afferent input. The decreased serotonin concentrations in the BG nuclei in PD may contribute to depressed GP activity and enhance the emergence of BG pathological synchronous oscillations. We therefore suggest that future therapeutics of PD should be directed towards restoration of normal serotonin levels in BG nuclei. Page 3 of 43