RESUMEN
Anomalous patterns of synchronization between basal ganglia and cortex underlie the symptoms of Parkinson's disease. Computational modeling studies suggest that changes in cortical feedback loops involving trans-striatal and trans-subthalamic circuits bring up this anomalous synchronization. We asked whether striatal outflow synchronizes globus pallidus neurons with cortical activity in a rat model of Parkinson's disease. We found that striatal firing is highly increased in rats with chronic nigrostriatal lesion and that this hyperactivity can be reduced by locally infusing a competitive NMDA receptor antagonist. Moreover, NMDA receptor-dependent striatal output had frequency dependent effects on distinct pathological patterns of cortico-pallidal coupling. Blockade of striatal NMDA receptors almost completely abolished an anomalous ~1Hz cortico-pallidal anti-phase synchronization induced by nigrostriatal degeneration. Moreover, under striatal NMDA receptor blockade, synchronization with 2.5-5Hz cortical oscillations falls to negligible levels and oscillations at 10-20Hz are markedly attenuated, whereas beta synchronization (with a peak at ~26Hz) is marginally reduced. Thus, tonic activation of striatal NMDA receptors allows different forms of anomalous oscillations along the cortico-striato-pallidal axis. Moreover, the frequency dependent effects of NMDA receptors suggest that low and high frequency parkinsonian oscillations stem from partially different mechanisms. Finally, our results may help to reconcile views about the contributions of changes in firing rate and oscillatory synchronization to Parkinson's disease symptoms by showing that they are related to each other.
Asunto(s)
Ondas Encefálicas , Corteza Cerebral/fisiopatología , Sincronización de Fase en Electroencefalografía , Globo Pálido/fisiopatología , Neostriado/fisiopatología , Enfermedad de Parkinson/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Globo Pálido/metabolismo , Masculino , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Up states are a hallmark of striatal physiology. Spontaneous activity in the thalamo-cortical network drives robust plateau depolarizations in the medium spiny projection neurons of the striatum. Medium spiny neuron firing is only possible during up states and is very tightly regulated by dopamine and NMDA receptors. In a rat model of Parkinson's disease the medium spiny neurons projecting to the globus pallidus (indirect pathway) show more depolarized up states and increased firing. This is translated into abnormal patterns of synchronization between the globus pallidus and frontal cortex, which are believed to underlie the symptoms of Parkinson's disease. Here we review our work in the field and propose a mechanism through which the lack of D2 receptor stimulation in the striatum allows the establishment of fixed routes of information flow in the cortico-striato-pallidal network.