Dissociation of impulsive traits by subthalamic metabotropic glutamate receptor 4

Behavioral strategies require gating of premature responses to optimize outcomes. Several brain areas control impulsive actions, but the neuronal basis of natural variation in impulsivity between individuals remain largely unknown. Here, by combining a Go/No-Go behavioral assay with resting state (rs) functional MRI in mice, we identified the subthalamic nucleus (STN), a known gate for motor control in the basal ganglia, as a major hot spot for trait impulsivity. In vivo recorded STN neural activity encoded impulsive action as a separable state from basic motor control, characterized by decoupled STN/Substantia nigra pars reticulata (SNr) mesoscale networks. Optogenetic modulation of STN activity bi-directionally controlled impulsive behavior. Pharmacological and genetic manipulations showed that these impulsive actions are modulated by metabotropic glutamate receptor 4 (mGlu4) function in STN and its coupling to SNr in a behavioral trait-dependent manner, and independently of general motor function. In conclusion, STN circuitry multiplexes motor control and trait impulsivity, which are molecularly dissociated by mGlu4. This provides a potential mechanism for the genetic modulation of impulsive behavior, a clinically relevant predictor for developing psychiatric disorders associated with impulsivity.

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Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

Journal of Pharmacological Sciences ◽

10.1254/jphs.09011fp ◽

2009 ◽

Vol 110 (3) ◽

pp. 315-325 ◽

Cited By ~ 12

Author(s):

Gentaroh Suzuki ◽

Hiroko Kawagoe-Takaki ◽

Takao Inoue ◽

Toshifumi Kimura ◽

Hirohiko Hikichi ◽

...

Keyword(s):

Glutamate Receptor ◽

Mouse Brain ◽

Metabotropic Glutamate Receptor ◽

Receptor Occupancy ◽

Receptor Subtype ◽

Metabotropic Glutamate

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In vivo positron emission tomography imaging with [11C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-010-1723-7 ◽

2011 ◽

Vol 38 (6) ◽

pp. 1083-1094 ◽

Cited By ~ 39

Author(s):

Christine DeLorenzo ◽

Matthew S. Milak ◽

Kathleen G. Brennan ◽

J. S. Dileep Kumar ◽

J. John Mann ◽

...

Keyword(s):

Positron Emission Tomography ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Positron Emission Tomography Imaging ◽

Emission Tomography ◽

Receptor Subtype ◽

Tomography Imaging ◽

Metabotropic Glutamate ◽

Positron Emission

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Metabotropic glutamate receptor agonist-induced hyperpolarizations in rat basolateral amygdala neurons: receptor characterization and ion channels

Journal of Neurophysiology ◽

10.1152/jn.1996.76.5.3059 ◽

1996 ◽

Vol 76 (5) ◽

pp. 3059-3069 ◽

Cited By ~ 28

Author(s):

K. H. Holmes ◽

N. B. Keele ◽

V. L. Arvanov ◽

P. Shinnick-Gallagher

Keyword(s):

Dicarboxylic Acid ◽

Glutamate Receptor ◽

Basolateral Amygdala ◽

Metabotropic Glutamate Receptor ◽

Outward Current ◽

Channel Blockers ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Metabotropic Glutamate ◽

Outward Currents

1. Metabotropic glutamate receptor (mGluR)-agonist-induced hyperpolarizations and corresponding outward currents were analyzed in basolateral amygdala (BLA) neurons in rat brain slice preparations with current-clamp and single-electrode voltage-clamp recording to characterize the mGluR subtype(s) and the ion channel(s) mediating this response. 2. The mGluR agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) induced a membrane hyperpolarization or outward current in BLA neurons in a concentration-dependent manner (median effective concentration = 34 microM; range = 10-200 microM); the 1S,3R-ACPD hyperpolarizations are recorded in 89% of neurons that accommodate or cease firing in response to a 400-ms depolarizing current injection (0.5 nA). 3. mGluR agonists elicited hyperpolarizations or outward currents in a concentration-dependent manner in the following rank order of potency: (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I) > 1S,3R-ACPD > (s)-4-carboxyphenylglycine = (RS)-4-carboxy-3-hydroxyphenylglycine (4C3HPG) > L-aminophosphonobutyric acid > (1S,3S)-1-amino-cyclopentane-1,3-dicarboxylic acid. In contrast, the mGluR agonists quisqualate and ibotenate induced only depolarizations in the presence of D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione in BLA neurons. 4. The 1S,3R-ACPD-induced outward current is mediated through a large-conductance calcium-dependent potassium (BK) conductance. The BK channel blockers iberiotoxin and charybdotoxin blocked the response, as did the potassium channel blockers tetraethylammonium and 4-aminopyridine; the small-conductance calcium-activated potassium channel blocker apamin did not affect the response. 5. The mGluR-agonist-induced hyperpolarization is blocked in amygdala slices from animals pretreated with pertussis toxin (PTX). 1S,3R-ACPD hyperpolarizations were recorded in neurons contralateral but not ipsilateral to the site of PTX injection. 6. The antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG, 500 microM) reduced significantly the 1S,3R-ACPD-induced hyperpolarization. 7. In conclusion, the relative potency of L-CCG-I and 4C3HPG in evoking only hyperpolarizations (outward currents) in accommodating neurons, and the observation that MCPG (500 microM) reduces the hyperpolarization, suggest that a group-II-like mGluR underlies the hyperpolarizing response. The mGluR-induced response is sensitive to iberiotoxin and to pretreatment with PTX, suggesting activation of BK channels through a group II mGluR linked to a PTX-sensitive G protein in BLA neurons.

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