Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Thiele, Sherri L.; Chen, Betty; Lo, Charlotte; Gertler, Tracey S.; Warre, Ruth; Surmeier, James D.; Brotchie, Jonathan M.; Nash, Joanne E.

doi:10.1016/j.nbd.2014.08.006

Cited by 78 publications

(75 citation statements)

References 87 publications

(148 reference statements)

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“…Crossing projections likely facilitate the observed coupling of dopamine transients. Moreover, our findings provide additional insight into recently reported receptor alterations (25)(26)(27)(28)(29), showing that the lesioned hemisphere is not completely dopamine-deprived. Low concentrations released from contralateral projections, such as those reported here after AMPH administration, likely influence receptor sensitivity in the lesioned hemisphere, and should be accounted for in future studies.…”

Section: Discussionsupporting

confidence: 74%

“…A hemiparkinsonian state can be modeled with unilateral 6-hydroxydopamine (6-OHDA) lesions, and recent studies have described alterations in synaptic signaling following dopamine depletion (25)(26)(27)(28)(29). If contralateral dopamine projections have functional significance, then dopamine arising from these intact projections may influence signaling in the lesioned hemisphere (30).…”

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confidence: 99%

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Cross-hemispheric dopamine projections have functional significance

Fox

Mikhailova

Bass

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson's disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine-lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres.dopamine | voltammetry | synchrony | nucleus accumbens | dorsal striatum D opamine neurotransmission modulates arousal and motivation, and is important to the expression of reward-seeking behavior. Dopamine is released on a subsecond timescale during unexpected reward (1, 2), and becomes time-locked to cues that predict reward (3-7). Dopamine transients in the nucleus accumbens (NAc) occur as a result of cell firing in the ventral tegmental area (VTA) (8, 9), and in rats reach concentrations of 50-200 nM before returning to baseline (10, 11). Striatal dopamine transients also occur spontaneously during periods of rest (10, 11), reflecting endogenous dopamine modulation. The magnitude and frequency of dopamine transients increase in response to drugs of abuse (12, 13), which is thought to contribute to their reinforcing properties (14). Although numerous studies have summarized the function of dopamine circuits in reward-based behaviors (15, 16) and motor control (17-19), anatomic descriptions of dopamine projections are conflicting (20-23). Recent evidence suggests that some dopamine neurons project contralateral to their origin (22, 23), contradictory to the uncrossed dopamine system described previously (20, 21). To date, the significance of contralaterally projecting dopamine neurons, and how they may contribute to cross-hemispheric signaling, have not been established.A potential role for contralateral dopamine projections emerged in a recent study on brain stimulation reward (24). When rats were trained to self-stimulate the VTA, infusion of dopamine receptor antagonists in the NAc suppressed stimulation. This effect was seen whether the infusion was contralateral or ipsilateral to the stimulation site, reflecting cross-hemispheric modulation of the behavior. Furthe...

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

Cross-hemispheric dopamine projections have functional significance

Fox

Mikhailova

Bass

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It is known that decreased inputs to the striatum are able to alter corticostriatal plasticity (22,23). Therefore, we hypothesized that the relative corticostriatal functional disconnection is also able to impair corticostriatal plasticity in HD.…”

Section: Q97mentioning

confidence: 96%

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

Molero

Arteaga-Bracho

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

115

100

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Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington’s disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-CreERT2 mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97CRE). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.

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“…R. Soc. B 370: 20140184 transfection with a bacterial artificial chromosome allows the expression of the enhanced Green Fluorescent Protein selectively on the direct or the indirect output pathways [19]. In control mice, bidirectional synaptic plasticity (LTD and LTP) was induced, resulting in a significant change in the amplitude of excitatory postsynaptic potentials in each direction in both striatal output pathways.…”

Section: (B) Long-term Depressionmentioning

confidence: 99%

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

Calabresi

Ghiglieri

Mazzocchetti

et al. 2015

Phil. Trans. R. Soc. B

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The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.

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Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Cited by 78 publications

References 87 publications

Cross-hemispheric dopamine projections have functional significance

Cross-hemispheric dopamine projections have functional significance

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

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