RESUMEN
Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.
Asunto(s)
Hipocampo/metabolismo , Interneuronas/metabolismo , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Animales , Modelos Animales de Enfermedad , Potenciales Evocados/fisiología , Masculino , Ratones , Ratones Noqueados , Vías Nerviosas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Transducción de Señal/fisiología , Ritmo Teta/fisiologíaRESUMEN
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.
Asunto(s)
Ganglios Basales/fisiología , Relojes Biológicos/fisiología , Cuerpo Estriado/fisiología , Activación del Canal Iónico/fisiología , Animales , Ganglios Basales/efectos de los fármacos , Cuerpo Estriado/citología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Humanos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The main clinical manifestations of Parkinson's disease are caused by alterations of basal ganglia activity that are tied in with the progressive loss of mesencephalic dopaminergic neurons. Recent theoretical and modeling studies have suggested that changes in resting neuronal activity occurred later in the course of the disease than those evoked by phasic cortical input. However, there is no empirical support for this proposal. Here we report a marked increase in the responsiveness of globus pallidus neurons to electrical motor cortex stimulation, in the absence of noticeable changes in resting activity, in anesthetized rats that had consistently shown a deficit in forelimb use during behavioral testing before the experiments, and had approximately 45% dopamine neurons spared in the substantia nigra. Pallidal neurons were also over-responsive to motor cortex stimulation and lost spatial selectivity for cortical inputs in rats with extensive nigrostriatal damage. After partial lesions, over-responsiveness was mainly due to an increased proportion of neurons showing excitatory responses, while extensive lesions led to an increased likelihood of inhibitory responding neurons. Changes in resting neuronal activity, comprising pauses disrupting tonic discharge, occurred across different global brain states, including an activated condition which shares similarities with natural patterns of cortical activity seen in awake states and rapid eye-movement sleep, but only after massive nigrostriatal degeneration. These results suggest that a loss of functional segregation and an abnormal temporal encoding of phasic cortical inputs by globus pallidus neurons may contribute to inducing early motor impairment in Parkinson's disease.
Asunto(s)
Potenciales de Acción/fisiología , Lateralidad Funcional/fisiología , Globo Pálido/patología , Globo Pálido/fisiopatología , Neuronas/fisiología , Trastornos Parkinsonianos/patología , Animales , Conducta Animal , Mapeo Encefálico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Masculino , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Ratas , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.