Synaptic integration and intrinsic firing properties of basal ganglia neurons

National Institute Of Neurological Disorders And Stroke

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Abstract

Research in the Cellular Neurophysiology Section focuses on the principles of excitability and integration of neurons in the midbrain dopamine system. Recently our laboratory has undergone major efforts to understand how dopamine signaling in the striatum is shaped by ligand-gated receptors that are present on the dopaminergic axon terminals. Although the role of the axons of dopaminergic neurons is to transmit somatic information, their terminals also receive local input directly from acetylcholine-releasing neurons that may influence striatal dopamine release. How this communication occurs between cells that bypasses dendrites is an open question. In a recent published study from our laboratory (Kramer et al, Neuron 2022), we addressed this question using direct electrophysiological patch recording techniques to measure the subthreshold membrane voltage from the dopaminergic neuron axons within the striatum of adult mice. Although anatomical studies have shown that dopaminergic axons largely lack classic synapses, our data show that signaling onto axons of dopaminergic neurons was functionally similar to signaling at traditional dendritic synapse. In addition, we examined integration of spontaneous cholinergic inputs onto axons. We found that the spontaneous cholinergic inputs in some cases can initiate spontaneous action potentials generated locally in axons. In a related collaborative study with the laboratory of Dr. Pascal Kaeser at Harvard Medical School, our laboratory also contributed perforated patch data from dopaminergic axons demonstrating that activation of axonal nicotinic receptors by synchronous optical stimulation of cholinergic interneurons can result in locally-generated axonal action potentials that may underlie striatal dopamine release (Liu et al., Science 2022). Together, these observations go against the classical notion of unidirectional flow of information in the nervous system. Instead, they demonstrate that similar to dendrites and soma, the axons may be important sites for the integration and generation of dopamine signaling. Thus, these studies establish framework for understanding the flow of information in the dopaminergic neurons pointing to possible new targets for treating substance use disorders and 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.