I_H 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 ∼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.

Visual-Induced Excitation Leads to Firing Pauses in Striatal Cholinergic Interneurons

“…The "PSP area" was calculated as the sum of all positive values from 80 ms after the light flash to the AHP start, and the "AHP area" was the absolute value of the sum of all negative values from the AHP start to end. PSP and AHP areas of traces obtained in vitro were derived as previously described (Oswald et al, 2009). Assessment of spiking activity.…”

“…This pattern persisted in the presence of the GABA A and GABA B receptor antagonists, gabazine (10 M) and (2S)-3-([(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl)(phenylmethyl)phosphinic acid (CGP55845) (1 M), respectively (n ϭ 6) (Fig. 8d), and when the NMDA receptor antagonist AP5 (50 M) was added additionally (n ϭ 2), indicating that it was intrinsically generated (Oswald et al, 2009). …”

“…Upon the relaxation of depolarizing synaptic currents, the membrane potential is dominated by the slow AHP-type Ca 2ϩ -activated K ϩ currents (I sAHP ) (Goldberg and Wilson, 2005) and will hyperpolarize. Small, brief subthreshold depolarizations in response to cortical synaptic inputs are often followed by AHPs , where the principal mechanism is the transient deactivation of the I H (Oswald et al, 2009). Thus, CINs appear to possess multiple intrinsic mechanisms to generate membrane potential hyperpolarizations following excitation that function over a broad range of magnitudes and timescales.…”

“…Strong intrastriatal stimulation was required to induce synchronized CIN firing and elicit this effect; how this mechanism is engaged in vivo and acquired through learning is yet to be determined. Finally, we have reported that membrane depolarization of CINs induced by glutamatergic inputs can trigger an intrinsic afterhyperpolarization (AHP) that suppresses spike firing for Ͼ200 ms Oswald et al, 2009).…”

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

“…Striatal cholinergic interneurons express several currents that could induce accommodation, including voltage-dependent potassium currents with properties similar to I M (Song et al, 1998;Bennett et al, 2000), and calcium-dependent potassium currents that mediate a medium (mAHP) and a slow (sAHP) AHP during excitation (SK and I sAHP , respectively) (Goldberg and Wilson, 2005). Barium blocks several potassium currents, including SK, I M , and a hyperpolarization-activated current (K IR ) that amplifies sAHP in cholinergic interneurons (Wilson, 2005), but spares others, including some components of I sAHP (Goldberg et al, 2009) and I h , another hyperpolarization-activated depolarizing current that shapes the AHPs (Deng et al, 2007;Oswald et al, 2009). Thus, as a first approach toward characterizing the mechanism involved in accommodation, we asked whether barium impairs accommodation in control striatal cholinergic interneurons.…”