Dopamine D2-Like Receptors Modulate Intrinsic Properties and Synaptic Transmission of Parvalbumin Interneurons in the Mouse Primary Motor Cortex

Cousineau, Jérémy; Lescouzères, Léa; Taupignon, Anne; Delgado-Zabalza, Lorena; Valjent, Emmanuel; Baufreton, Jérôme; Bon-Jégo, Morgane Le

doi:10.1523/eneuro.0081-20.2020

Cited by 32 publications

(31 citation statements)

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“…An acute application of DA did not affect the excitability of PTNs in both controls and in 6-OHDA mice. These results are consistent with recent findings that dopaminergic modulation of pyramidal neurons is mainly mediated indirectly by parvalbumin-expressing interneurons in M1 (Vitrac et al, 2014;Cousineau et al, 2020).…”

Section: Discussionsupporting

confidence: 93%

“…An acute application of DA did not rescue altered intrinsic excitability of PTNs and had minimal effects to intrinsic properties of ITNs in 6-OHDA mice. This indicated that loss of dopaminergic neuromodulation does not play a major role in the intrinsic adaptations of M1 pyramidal neurons in parkinsonian state, which is consistent with recent findings that dopaminergic modulation of pyramidal neurons is mainly mediated indirectly by parvalbumin-expressing interneurons in M1 (Vitrac et al, 2014;Cousineau et al, 2020). Thus, we propose that circuitry mechanisms underlie cellular adaptions in M1 in parkinsonian state.…”

Section: Discussionsupporting

confidence: 91%

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Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

Chen

Kim

Chu

2020

Preprint

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The hypokinetic motor symptoms of Parkinsons disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine alters the cellular properties of motor cortical neurons in PD remains undefined. We induced experimental parkinsonism in adult C57BL6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine, into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the motor cortical layer 5b was greatly decreased following the degeneration of midbrain dopaminergic neurons; but the intratelencephalic neurons (ITNs) were not affected. The cell-type-specific intrinsic adaptations were associated with a significant broadening of the action potentials in PTNs but not in ITNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability and broadened action potentials were largely caused by a disrupted function of the large conductance, Ca2+-activated K+ channels. The restoration of dopaminergic neuromodulation failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data show cell-type-specific decreases of the excitability of M1 pyramidal neurons following the loss of midbrain dopaminergic neurons. Thus, intrinsic adaptations in the motor cortex, together with pathological basal ganglia inhibition, underlie the decreased motor cortical output in parkinsonian state and exacerbate parkinsonian motor deficits

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

Chen

Kim

Chu

2020

Preprint

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“…In contrast to D1-like receptor expression, D2-like receptor expression does not decrease with aging in human hippocampus ( Seaman et al, 2019 ) and rodent area CA3 ( Amenta et al, 2001 ). D2-like dopamine receptors are mainly expressed on interneurons in the cortex ( Cousineau et al, 2020 ) and hippocampus ( Andersson et al, 2012b ) D2-like receptors inhibit adenylate cyclase activity and although this could reduce excitability, D2-like receptor activation increases fast-spiking interneuron activity and GABAergic inhibition ( Tseng and O’Donnell, 2007 ; Tomasella et al, 2018 ), probably through a β-Arrestin2–dependent inhibition of Akt and activation of Gsk3β ( Urs et al, 2016 ). In Addition, D2-like receptors can activate receptor tyrosine kinase-ERK signaling ( Kim et al, 2006 ; Beaulieu et al, 2011 ), which is critical for dopamine-induced enhancement of γ oscillation in young rats ( Xie et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice

Wang

Jin

Guo

et al. 2022

Front. Aging Neurosci.

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AimNeural network oscillation at gamma frequency band (γ oscillation, 30–80 Hz) is synchronized synaptic potentials important for higher brain processes and altered in normal aging. Recent studies indicate that activation of dopamine 4 receptor (DR4) enhanced hippocampal γ oscillation of young mice and fully recovered the impaired hippocampal synaptic plasticity of aged mice, we determined whether this receptor is involved in aging-related modulation of hippocampal γ oscillation.MethodsWe recorded γ oscillations in the hippocampal CA3 region from young and aged C57bl6 mice and investigated the effects of dopamine and the selective dopamine receptor (DR) agonists on γ oscillation.ResultsWe first found that γ oscillation power (γ power) was reduced in aged mice compared to young mice, which was restored by exogenous application of dopamine (DA). Second, the selective agonists for different D1- and D2-type dopamine receptors increased γ power in young mice but had little or small effect in aged mice. Third, the D4 receptor (D4R) agonist PD168077 caused a large increase of γ power in aged mice but a small increase in young mice, and its effect is blocked by the highly specific D4R antagonist L-745,870 or largely reduced by a NMDAR antagonist. Fourth, D3R agonist had no effect on γ power of either young or aged mice.ConclusionThis study reveals DR subtype-mediated hippocampal γ oscillations is aging-related and DR4 activation restores the impaired γ oscillations in aged brain, and suggests that D4R is the potential target for the improvement of cognitive deficits related to the aging and aging-related diseases.

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“…For example, D2R stimulation in the prefrontal cortex of monkeys engaged in a cognitive task increases working memory encoding at both single neuron and population levels (Ott and Nieder, 2017 ). The resting and active properties of PV+ GABAergic interneurons are targets of D2R modulation (Cousineau et al, 2020 ). Moreover, a schizophrenia-related genetic deletion reduces the ability of D2Rs to gate the inhibition of excitatory neurons through PV+ inhibitory neurons in the cerebral cortex (Choi et al, 2018 ), providing a neural mechanism linking D2R-mediated function specifically in GABAergic interneurons to the pathophysiology of psychosis.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

Lee

Graham²,

Noble³

et al. 2022

Front. Behav. Neurosci.

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Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

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Dopamine D2-Like Receptors Modulate Intrinsic Properties and Synaptic Transmission of Parvalbumin Interneurons in the Mouse Primary Motor Cortex

Cited by 32 publications

References 50 publications

Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice

Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

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