Electrical Signaling in Dendritic Branches

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.

Grant Number: 1R21NS138991-01
NIH Institute/Center: NIH
Principal Investigator: SRDJAN ANTIC