Reduction of an Afterhyperpolarization Current Increases Excitability in Striatal Cholinergic Interneurons in Rat Parkinsonism

Abstract

Striatal cholinergic interneurons show tonic spiking activity in the intact and sliced brain, which stems from intrinsic mechanisms. Because of it, they are also known as "tonically active neurons" (TANs). Another hallmark of TAN electrophysiology is a pause response to appetitive and aversive events and to environmental cues that have predicted these events during learning. Notably, the pause response is lost after the degeneration of dopaminergic neurons in animal models of Parkinson's disease. Moreover, Parkinson's disease patients are in a hypercholinergic state and find some clinical benefit in anticholinergic drugs. Current theories propose that excitatory thalamic inputs conveying information about salient sensory stimuli trigger an intrinsic hyperpolarizing response in the striatal cholinergic interneurons. Moreover, it has been postulated that the loss of the pause response in Parkinson's disease is related to a diminution of I sAHP , a slow outward current that mediates an afterhyperpolarization following a train of action potentials. Here we report that I sAHP induces a marked spike-frequency adaptation in adult rat striatal cholinergic interneurons, inducing an abrupt end of firing during sustained excitation. Chronic loss of dopaminergic neurons markedly reduces I sAHP and spike-frequency adaptation in cholinergic interneurons, allowing them to fire continuously and at higher rates during sustained excitation. These findings provide a plausible explanation for the hypercholinergic state in Parkinson's disease. Moreover, a reduction of I sAHP may alter synchronization of cholinergic interneurons with afferent inputs, thus contributing to the loss of the pause response in Parkinson's disease.

Acute nigro-striatal blockade alters cortico-striatal encoding: An in vivo electrophysiological study

“…Indeed, cholinergic neurons are quite independent of cortical control (i.e. less affected by SWA), whilst showing an augmented activity in Parkinsonian state, in both the chronic (Sanchez et al, 2011) and acute condition (Fino et al, 2007;present data). We hypothesize that they maintain a surrogate role as feedback circuit not necessarily involving the cortex.…”

Cholinergic modulation of striatal microcircuits

“…Another feature of ChIs is a long pause in the tonic firing that follows bursts of action potentials. Their intrinsic properties allow ChIs to fire in regular, irregular, and in burst fashion interspersed with long pauses (Bennett et al., ; Goldberg & Wilson, , ; Wilson, ; Sanchez et al., ). During a burst, a subthreshold accumulation of calcium through Ca V 1 channels recruits an additional potassium current that, in turn, produces a long‐lasting (several seconds) hyperpolarization (sAHP) (Wilson & Goldberg, ; Tubert et al., ).…”

Modulation of Kv7 channels and excitability in the brain

“…The identity of the potassium channel responsible for the slow AHP had proven elusive until recently. While Kv7 has been suggested as a contributor of sAHP, as afferent cholinergic stimulation reduces effective sAHP amplitude [107], one confounding factor discredited its involvement: the sAHP is active at membrane potentials more negative than M-current activity is typically observed. Activation of the sAHP is known to have a Ca 2+ dependent component, and neuronal calcium sensor proteins such as hippocalcin have been implicated in the activation of potassium channels that constitute the sAHP [108,109].…”