Classification of Neuronal Subtypes in the Globus Pallidus External Segment The Globus pallidus external segment (GPe) is a region of the basal ganglia that has key functions in action control and learning. The GABAergic cells that comprise the bulk of neurons within the GPe show robust spontaneous action potential firing even in brain slices. While in the past this nucleus was often viewed as a relatively homogeneous relay station for information passing through the C-BG loops, it is now clear that the GPe has a more central role in coding for action control. Altered activity within the GPe is a key feature of hypokinesia in Parkinson's Disease. It is also now clear that there is considerable heterogeneity of the activity patterns, molecular markers and projection targets of GPe neurons. Indeed, with projections to the striatum (the arkypallidal projection) as well as to subthalamic nucleus and other basal ganglia nuclei, the tonically-active GPe neurons exert ongoing influences on all parts of the Cortico-Basal Ganglia circuitry. Thus, it is important to understand GPe function and drug actions within this part of the circuit. We have classified GPe neuronal subtypes based on their electrophysiological and molecular characteristics. One goal of this study was to develop a classification system that could be used in the absence of expression of transgenic molecular marker-expressing mice. To this end, we used unbiased cluster analysis to sort unlabeled GPe neurons based on brain slice electrophysiological data. While other investigators have classified neurons labeled for expression of many molecular markders, we also used mice expressing the FoxP2 transcription factor to provide a molecular identifier for an important neuronal subclass. We have also characterized the distribution of different neuronal subtypes in several GPe subregions. Consistent with other laboratories, we can classify at least 3 subtypes of GPe neurons based on the firing rate and the amplitude of the hyperpolarization-induced sag potential. We then checked the accuracy of this classification scheme with the presence of molecular markers in transgenic mice, and immunostaining for the parvalbumin protein. The classification scheme corresponded to molecular-expression-based schemes. It also allowed us to classify and separate 2 subtypes of neurons whose firing is inhibited by ethanol, as we showed in a previous study. Overall, these findings will allow us to identify the different GPe neuronal subtypes in non-transgenic mice and in related species because transgenic reporter mice are not available. Ethanol Actions at GABAergic Synapses in striatum and striatal efferents To better understand how EtOH alters the function of the Basal Ganglia we are examining effects on GABAergic synapses within the striatum and in striatal efferent projections to the GPe and the substantia nigra pars reticulate (SNr). We examined arkypallidal GABAergic synapses pathway by which GPe neurons inhibit striatal medium spiny projection neurons (MSNs) by expressing channel rhodopsin 2 (ChR2) in Npas1 Cre-positive GPe neurons and recording from MSNs in striatal brain slices. We have observed inhibition of GABAergic oIPSCs by acute EtOH. Inhibition of arkypallidal neuronal firing by EtOH may contribute to the disinhibition of MSNs that we have postulated as a feature of intoxication. We examined ethanol effects on GABAergic synapses made by direct- and indirect pathway MSNs in the GPe and SNr. This was accomplished by expressing ChR2 in direct and indirect pathway neurons using the D1- and A2A-Cre mice, respectively and recording GABAergic synaptic responses in the GPe and SNr. Interestingly, light activation of striatal afferents in D1-Cre neurons expressing ChR2 produced robust oIPSCs in both GPe and SNr neurons. Thus, the collateral axons of the direct pathway neurons appear to be capable of efficacious transmission within the indirect pathway, as previously noted in the ventral pallidum. This pathway must be considered when developing models of basal ganglai function. Acute exposure to EtOH inhibits MSN-SNr direct pathway GABAergic synapses examined in D1-Cre mice. Acute EtOH exposure has no effect on indirect pathway synapses or GABAergic D1-MSN collaterals in GPe. Thus, the net effect of ethanol on key components of the striatal-basal ganglia circuitry appears to be disinhibition of the striatum that may contribute to enhancement of habitual behaviors, and inhibition of striatonigral synapses that may reduce behavioral activation in response to cortical drive or sensory input.
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