Synaptic integration and intrinsic firing properties of basal ganglia neurons

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

The Cellular Neurophysiology Section studies the physiology of neurons located in the midbrain dopamine system and as well as their circuit integration in the basal ganglia. Our laboratory has focused on understanding how dopamine signaling in the striatum is shaped by ligand-gated receptors on dopaminergic axon terminals. In particular, the axons of dopaminergic cells receive input from acetylcholine-releasing neurons within the striatum that may influence dopamine release. In addition, we have demonstrated that the dopaminergic axons express GABA-A receptors that many locally inhibit striatal dopamine release. Recently, we have been examining how axonal GABA-A receptors influence the integration of input arriving from local cholinergic interneurons to shape axonal excitability and dopamine release. In our analysis of axonal calcium influx using GCaMP in ex vivo tissue slices, we isolated the two main components of the axonal calcium signals one component resulting from direct axonal stimulation and a later component due to transmission onto axonal nicotinic receptors. We find that axonal GABA-A receptors inhibits directly-evoked axonal signal but has a stronger effect on the amplitude and speed of the nicotinic component. Using direct axonal recordings, we show that the GABA-A receptor positive allosteric modulator, diazepam, decreases the magnitude of subthreshold nicotinic input onto dopamine axons. In our studies examining the GABA-A receptor interaction with nicotinic receptors, we found show that picrotoxin potently blocks striatal nicotinic receptors at concentrations that have typically been used for physiology experiments suggesting that caution must be used when selecting GABA-A receptor antagonists. Together, our results highlight that striatal dopamine axons integrate information from cholinergic interneurons in a manner that is regulated by axonal GABAA receptors. In a separate project, we investigated the contribution of the sodium leak conductance, NALCN, to pacemaking in different dopamine neuron subpopulations. We found that NALCN contributes to firing in dopaminergic neurons located in the ventral tegmental area (VTA DANs), particularly those that project to medial and lateral nucleus accumbens. Specifically, we found acute pharmacological blockade of NALCN substantially slowed pacemaking in medial VTA DANs. Thus, NALCN is a primary driver of pacemaking in VTA DANs. In substantia nigra (SNc) DANs, however, we found that NALCN is functionally present but pacemaking in SNc DANs was unaffected by inhibition of NALCN. Instead, we show that NALCN reduces the gain of frequency-current plots of firing frequencies measured at rates slower than spontaneous firing. In separate experiments, we explored to role of the hyperpolarization-activated current (Ih) and found that simultaneous inhibition of NALCN and Ih resulted in significant reduction in pacemaker rate in SNc neurons. Thus, we found NALCN makes substantial contributions to driving pacemaking in VTA DAN subpopulations while in SNc DANs, NALCN is not critical for pacemaking but inhibition of this current makes cells more sensitive to hyperpolarizing stimuli. This study has been submitted for publication and was accepted at the Journal of Neuroscience (Cobb-Lewis et al. 2023). These findings will inform future efforts to obtain dopaminergic neuron subpopulation specific treatments in neuropsychiatric and motor disorders such as Parkinsons Disease. In a separate study, we have been investigating the role of the sodium leak conductance, NALCN, to slow spontaneous firing called pacemaking in different dopamine neuron subpopulations. We have found that while NALCN contributes to firing in substantia nigra neurons, the contribution of NALCN is much stronger in medial dopaminergic neurons, particularly those that project to medial nucleus accumbens. This study has been submitted for publication and is currently in revisions.