An increased gain in the cortico-striatal pathway is responsible for the abnormal activity induced downstream in the basal ganglia in dopamine depleted rats

ZOLD CL, POMATA PE, RIQUELME LA AND MURER MG

Washington DC

Congreso; Neuroscience 2008; 2008

Society for Neuroscience

Degeneration of the nigrostriatal pathway results in prominent oscillatory synchronization of basal ganglia activity (BG), which is thought to underlie the clinical manifestations of Parkinson?s disease. However, the mechanisms that lie behind this activity are still unclear. Studies based on functional connectivity have proposed that the oscillation and synchronicity may stem from a dysfunction of the cortical-subthalamic nucleus (STN) pathway, but no clear causal associations could be established. The globus pallidus (GP) is a critical link in the circuitry connecting the cerebral cortex with the BG output nuclei. It receives cortical inputs through the striatum (STR, inhibitory) and STN (excitatory). Our previous work has shown that, in high contrast to what is observed in control rats, most GP neurons are driven by inhibitory cortical inputs under both slow waves and cortical activation in dopamine depleted rats (Zold et al., 2007; Eur J Neurosci). Our hypothesis is that GP neurons? abnormal activity is caused by an increased gain of the cortico-STR-GP pathway, and that this hyperactivity could be modulated by local administration of an NMDA receptor antagonist (APV) in the STR. To test it, we tried to disrupt the cortico-STR pathway by infusing APV in the STR by reverse microdialysis. We recorded GP and striatal neurons in vivo with a multichannel silicon probe simultaneously with the cortical local filed potential under urethane anaesthesia in 6-OHDA-lesioned rats (a widespread model of Parkinsonism). In 6-OHDA-lesioned rats, APV 100μM reversibly reduced striatal neurons firing rate (191 ± 47 vs 92 ± 47 spikes/min per channel; multiunit activity; p0.05, n=11). These results suggest that: i) the NMDA receptor contributes to the spontaneous firing of striatal neurons in 6-OHDA-lesioned rats; ii) NMDA receptor dependent striatal activity allows the spreading to the GP of inhibitory activity driven by the cortex in dopamine depleted rats. This is, to our knowledge, the first direct demonstration of the mechanism underlying the pathological activity downstream the STR in parkinsonism, and suggests that the stimulation of striatal NMDA receptors play a key role in the augmentation of the cortico-STR-GP pathway in Parkinson disease. Funded by FONCYT, CONICET and UBA (Argentina).