Elsevier

Neuropharmacology

Volume 95, August 2015, Pages 468-476
Neuropharmacology

Dopaminergic and cholinergic modulation of striatal tyrosine hydroxylase interneurons

https://doi.org/10.1016/j.neuropharm.2015.03.036Get rights and content

Highlights

  • Striatal TH interneurons express calcium and sodium dependent plateau potentials.

  • The plateau potentials are enhanced by dopamine or agonists of D1/D5 DA receptors.

  • Plateau potentials are mediated by ICAN.

  • Striatal TH interneurons are also excited by ACh acting through Type 3 nicotinic receptors.

Abstract

The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2015). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulation of THINs in vitro. We found that the dominant effect of dopamine was a dramatic enhancement of the ability of THINs to generate long-lasting depolarizing plateau potentials (PPs). Interestingly, the same effect could also be elicited by amphetamine-induced release of endogenous dopamine suggesting that THINs may exhibit similar responses to changes in extracellular dopamine concentration in vivo. The enhancement of PPs in THINs is perhaps the most pronounced effect of dopamine on the intrinsic excitability of neostriatal neurons described to date. Further, we demonstrate that all subtypes of THINSs tested also express nicotinic cholinergic receptors. All THINs responded, albeit differentially, with depolarization, PPs and spiking to brief application of nicotinic agonists. Powerful modulation of the nonlinear integrative properties of THINs by dopamine and the direct depolarization of these neurons by acetylcholine may play important roles in mediating the effects of these neuromodulators in the neostriatum with potentially important implications for understanding the mechanisms of neuropsychiatric disorders affecting the basal ganglia.

Introduction

Until recently, the neostriatum has been thought to contain only a few types of GABAergic interneurons in comparison to the large diversity of GABAergic cell types in the neocortex or the hippocampus (Freund, 1996, Tepper et al., 2010, DeFelipe et al., 2013). This picture changed significantly with the introduction of transgenic reporter mouse lines that revealed the existence of 5 new electrophysiologically distinct cell types, more than doubling the number of interneuron classes recognized in this brain area (Ibáñez-Sandoval et al., 2010, Ibáñez-Sandoval et al., 2011; Unal et al., 2011). In addition to a neuropeptide Y (NPY) expressing neuron described in a NPY-GFP line (Ibáñez-Sandoval et al., 2011), the newly discovered interneurons include 4 additional types of GABAergic neurons that were termed TH-interneurons (THINs) reflecting their initial identification in a TH-EGFP strain (Ibáñez-Sandoval et al., 2010; Unal et al., 2011). The function of THINs remains unclear. Their small population size and connectivity place some important constraints on the possible function of these neurons. On particularly interesting possibility is that these neurons may distribute intra- and extrastriatal neuromodulatory signals to projection neurons.

In the neostriatum, dopamine (DA) and acetylcholine (ACh) are 2 major neuromodulators that exert pronounced effects on most functions of the basal ganglia. Here we investigated how these neuromodulators or control the intrinsic electrophysiological properties of THINs. Since preliminary experiments indicated that the most salient effect of these modulators was the triggering and enhancement of a semi-stable depolarizing state we characterized in more detail this important dynamic feature of THINs.

Section snippets

Subjects

We used transgenic mice Tg (Th-EGFP) DJ76Gsat/Mmmc (GENSAT; Gong et al., 2003), obtained from the Mutant Mouse Regional Resource Center at UCLA and bred in our colony at Rutgers for all experiments. Hemizygous progeny were mated to wild type FVB or Swiss Webster mice each generation thereafter. All offspring were genotyped from tail samples and only those expressing the EGFP transgene were used in these experiments. Henceforth these mice are referred to as EGFP-TH mice.

All procedures were

Electrophysiological and anatomical properties of striatal TH interneurons

Ex vivo whole-cell recordings were obtained in current clamp mode from fluorescent neurons in the striatum of adult EGFP-TH mice. In agreement with previously reported data (Ibáñez-Sandoval et al., 2010), several distinct subtypes of THINs could be characterized on the basis of their intrinsic electrophysiological properties (input resistance Rin), resting membrane potential (RMP), action potential duration at half-amplitude (AP50%), their ability or inability to maintain firing throughout

Discussion

The present experiments examined the effects of DA and ACh on striatal THINs. The first principal finding was that intrinsic PPs elicited by depolarizing pulses in Type I and Type II THINs were facilitated by DA acting through a D1/D5-like DA receptor, and that in Type I and Type II THINs that did not exhibit intrinsic PPs, as well as in Type IV THINs that were never observed to exhibit intrinsic PPs, these plateaus could be elicited by D1/D5 receptor stimulation. In all cases, the PPs were

Acknowledgments

This research was supported, in part, by NIH Grants 5R01NS034865 (J M T.), 1R01NS072950 (T K. and J.M. T.) and Rutgers University. We thank Fulva Shah and Parth Gandhi for excellent technical assistance and Leticia Maldonado for the biocytin reconstruction in Figure 1A.

References (47)

  • T. Aosaki et al.

    Effect of the nigrostriatal dopamine system on acquired neural responses in the striatum of behaving monkeys

    Science

    (1994)
  • T. Aosaki et al.

    Temporal and spatial characteristics of tonically active neurons of the primate's striatum

    J. Neurophysiol.

    (1995)
  • T. Aosaki et al.

    Acetylcholine–dopamine balance hypothesis in the striatum: an update

    Geriatr. Gerontol. Int.

    (2010)
  • L. Bao et al.

    Partial mitochondrial inhibition causes striatal dopamine release suppression and medium spiny neuron depolarization via H2O2 elevation, not ATP depletion

    J. Neurosci.

    (2005)
  • J. Baufreton et al.

    D5 (not D1) dopamine receptors potentiate burst- firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance

    J. Neurosci.

    (2003)
  • E. Bracci et al.

    Dopamine excites fast-spiking interneurons in the striatum

    J. Neurophysiol.

    (2002)
  • D. Centonze et al.

    Activation of dopamine D1-like receptors excites LTS interneurons of the striatum

    Eur. J. Neurosci.

    (2002)
  • D. Centonze et al.

    Receptor subtypes involved in the presynaptic and postsynaptic actions of dopamine in striatal interneurons

    J. Neurosci.

    (2003)
  • J. DeFelipe et al.

    New insights into the classification and nomenclature of cortical GABAergic interneurons

    Nat. Rev. Neurosci.

    (2013)
  • D.F. English et al.

    GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons

    Nat. Neurosci.

    (2012)
  • A. Figueroa et al.

    Muscarinic receptor involved in the subthreshold cholinergic actions of neostriatal spiny neurons

    Synapse

    (2002)
  • T.F. Freund et al.

    Interneurons of the hippocampus

    Hippocampus

    (1996)
  • J.A. Goldberg et al.

    Muscarinic modulation of striatal function and circuitry

    Handb. Exp. Pharmacol.

    (2012)
  • Cited by (0)

    1

    Present address: Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Av., Venustiano Carranza, San Luis Potosí, Mexico.

    2

    Present address: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

    View full text