IH current generates the afterhyperpolarisation following activation of subthreshold cortical synaptic inputs to striatal cholinergic interneurons

Abstract

Pauses in the tonic firing of striatal cholinergic interneurons emerge during reward-related learning and are triggered by neutral cues which develop behavioural significance. In a previous in vivo study we have proposed that these pauses in firing may be due to intrinsically generated afterhyperpolarisations (AHPs) evoked by excitatory synaptic inputs, including those below the threshold for action potential firing. The aim of this study was to investigate the mechanism of the AHPs using a brain slice preparation which preserved both cerebral hemispheres. Augmenting cortically evoked postsynaptic potentials (PSPs) by repetitive stimulation of cortical afferents evoked AHPs that were unaffected by blocking either GABA(A) receptors with bicuculline, or GABA(B) receptors with saclofen or CGP55845. Apamin (a blocker of small conductance Ca(2+)-activated K(+) channels) had minimal effects, while chelation of intracellular Ca(2+) with BAPTA reduced the AHP by about 30%. In contrast, blocking hyperpolarisation and cyclic nucleotide activated (HCN) cation current (I(H)) with ZD7288 or Cs(+) diminished the size of the AHPs by 60% and reduced the proportion of episodes that contained this hyperpolarisation. The reversal potential (20 mV) and voltage dependence of the AHPs were consistent with the hypothesis that a transient deactivation of I(H) caused most of the AHP at hyperpolarised potentials, while the slow AHP-type Ca(2+)-activated K(+) channels increasingly contributed at more depolarised membrane potentials. Subthreshold somatic current injections yielded similar AHPs with a median duration of approximately 700 ms that were not affected by firing of a single action potential. These results indicate that transient deactivation of HCN channels evokes pauses in tonic firing of cholinergic interneurons, an event likely to be elicited by augmentation of afferent synaptic inputs during learning.