Wednesday, January 15, 2025
1/15/2025
Spiny projection neurons (SPNs) carry much of the weight of the basal ganglia (BG) information processing. One cell type (dSPNs) contributes to the Direct BG, while the other cell type (iSPNs) projects to the Indirect BG pathway. The imbalance across these two neural pathways is associated with either hypokinetic disorders such as Parkinson's disease (PD), or hyperkinetic disorders such as Huntington's and tics. We will test two hypotheses. >>Hypothesis-1 is grounded in intracellular recordings obtained from the cell bodies of dSPNs and iSPNs, revealing consistent physiological disparities between the two cell types. Our hypothesis posits that these observed physiological distinctions in cell bodies stem from underlying differences in dendritic properties. To validate this hypothesis, we plan to conduct recordings of dendritic electrical signals, including synaptic and AP waveforms, and dendritic regenerative potentials (dendritic spikes), within primary, secondary, and tertiary branches of individual neurons belonging to either the dSPN or iSPN subtype. >>Hypothesis-2 is rooted in the findings of several translational studies demonstrating the protective effects of specific drugs, namely K+ channel blockers, on dopaminergic (DA) neurons in animal models of PD. Our hypothesis posits that the systemic administration of these drugs not only shields DA neurons but also impacts the dendrites and axons of striatal SPNs, which project directly or indirectly to DA cells. We propose that the experimental use of K+ channel blockers in PD therapies significantly alters the electrical signaling within striatal dendrites. To explore this, we pose crucial questions: Do these drugs facilitate or impede the generation of local dendritic NMDA spikes and complex spikes (involving both dendritic and axonal spikes)? Does their pharmacological impact vary between different subtypes of SPNs? If so, it implies that drugs safeguarding DA neurons in PD models also influence the balance between the Direct and Indirect BG pathways. The adjustment of the balance between the “GO” and “NOGO” pathways is a primary objective in experimental therapies for BG disorders. Our research aims to elucidate whether these protective K+ channel blockers could be employed to modulate the Direct and Indirect pathways. If substantiated, this discovery could potentially establish them as supplementary therapies, complementing approved treatments such as levodopa. Our study not only promises a physiological understanding of the functioning of these protective treatments, but also explores the potential of channel modulators in balancing the D/I pathways. Additionally, our proposal marks the pioneering effort in capturing dendritic electrical signaling in striatum through voltage imaging, bridging significant gaps in our comprehension of electrical signal processing within the principal projection neurons of the two BG pathways.
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