Identification of PSD-95 as a Regulator of Dopamine-Mediated Synaptic and Behavioral Plasticity

Yao, Wei‐Dong; Gainetdinov, Raul R.; Arbuckle, Margaret I.; Sotnikova, Tatyana D.; Cyr, Michel; Beaulieu, Jean‐Martin; Torres, Gonzalo E.; Grant, Seth G. N.; Caron, Marc G.

doi:10.1016/s0896-6273(04)00048-0

Cited by 346 publications

(327 citation statements)

References 83 publications

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“…The modulatory role of DA in synaptic plasticity is further supported by in vivo studies showing that repeated systemic exposure to psychostimulants facilitates LTP induction in the midbrain (Liu et al, 2005), reduces LTD in the nucleus accumbens (Thomas et al, 2001), and converts LTD into LTP in the striatum (Nishioku et al, 1999). Interestingly, enhanced LTP of the cortico-accumbal synapses was recently reported in DAT-KO mice, used as a genetic model of long-term exposure to psychostimulants (Yao et al, 2004). Altogether, these data and ours, demonstrating that both LTP and LTD are altered in hippocampal CA1 synapses, suggest that hyperdopaminergia mediates a loss of bidirectional synaptic plasticity in high-order pathways and strengthen the emerging consensus that drug addiction and memory processes may rely on similar cellular mechanisms (Nestler et al, 1993;Berke and Hyman, 2000;Hyman and Malenka, 2001;Malenka and Bear, 2004).…”

Section: Discussionmentioning

confidence: 85%

“…Besides their obvious hyperactivity, DAT-KO mice exhibit heightened rates of stereotypies and perseverative patterns of nongoal-directed behavior, distorting their motor, exploratory, and social behaviors Spielewoy et al, 2000b;Ralph et al, 2001;Rodriguiz et al, 2004). Based on their constitutive hyperdopaminergia, DAT-KO mice were used as a genetic model of long-term exposure to psychostimulants and were shown to exhibit an enhanced long-term potentiation (LTP) of the synaptic strength in the nucleus accumbens, a major component of the brain reward system (Yao et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Morice

Billard

Denis

et al. 2007

Neuropsychopharmacol

103

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Dopamine-mediated neurotransmission has been implicated in the modulation of synaptic plasticity and in the mechanisms underlying learning and memory. In the present study, we tested different forms of activity-dependent neuronal and behavioral plasticity in knockout mice for the dopamine transporter (DAT-KO), which constitute a unique genetic model of constitutive hyperdopaminergia. We report that DAT-KO mice exhibit slightly increased long-term potentiation and severely decreased long-term depression at hippocampal CA3-CA1 excitatory synapses. Mutant mice also show impaired adaptation to environmental changes in the Morris watermaze. Both the electrophysiological and behavioral phenotypes are reversed by the dopamine antagonist haloperidol, suggesting that hyperdopaminergia is involved in these deficits. These findings support the modulation by dopamine of synaptic plasticity and cognitive flexibility. The behavioral deficits seen in DAT-KO mice are reminiscent of the deficits in executive functions observed in dopamine-related neuropsychiatric disorders, suggesting that the study of DAT-KO mice can contribute to the understanding of the molecular basis of these disorders.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Morice

Billard

Denis

et al. 2007

Neuropsychopharmacol

103

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“…In a phenotype-driven, microarray-based screen for mechanisms underlying psychostimulantelicited plasticity, PSD-95 was identified as a regulator of DA signaling [85]. The level of PSD-95 is reduced in the striatum of several mouse models of DA supersensitivity, and mice lacking PSD-95 show enhanced behavioral responses to the psychostimulants cocaine and amphetamine [43,85].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…In both heterologous cells and cultured neurons, activation of NMDARs recruited D1 receptors to the plasma membrane via a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent mechanism, resulting in enhancement of D1-mediated cAMP accumulation [84]. These studies, while not entirely consistent mechanistically, all appear to support direct D1-NMDAR interaction.In a phenotype-driven, microarray-based screen for mechanisms underlying psychostimulantelicited plasticity, PSD-95 was identified as a regulator of DA signaling [85]. The level of PSD-95 is reduced in the striatum of several mouse models of DA supersensitivity, and mice lacking PSD-95 show enhanced behavioral responses to the psychostimulants cocaine and amphetamine [43,85].…”

mentioning

confidence: 99%

Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

Self Cite

110

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Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

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“…The microarray method allows high-throughput analysis of gene expression patterns (Khan et al, 1999;Lipshutz et al, 1999), and it is particularly useful for studying cocaineinduced gene expression changes (Bibb et al, 2001;Freeman et al, 2001a, b;Toda et al, 2002;McClung and Nestler, 2003;Yuferov et al, 2003;Tang et al, 2003;Yao et al, 2004;Albertson et al, 2004). Despite these studies, the gene expression profile induced by chronic cocaine through the DA D1 receptors remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Zhang

Tang

et al. 2005

Neuropsychopharmacol

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Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects of cocaine correlate with underlying changes in gene expression, we have used D1 receptor mutant and wild-type mice to identify chronic cocaine-induced gene expression changes mediated via the D1 receptors. We focused on the caudoputamen and nucleus accumbens, two key brain regions that mediate the long-term effects of cocaine. Our analyses demonstrate that repeated cocaine administration induces changes in the expression of 109 genes, including those encoding the stromal cell-derived factor 1, insulin-like growth factor binding protein 6, sigma 1 receptor, regulators of G-protein signaling protein 4, Wnt1 responsive Cdc42 homolog, Ca 2 þ /calmodulin-dependent protein kinase II a subunit, and cyclin D2, via the D1 receptors. Moreover, the seven genes contain AP-1 binding sites in their promoter regions. These results suggest that genes encoding certain extracellular factors, membrane receptors and modulators, and intracellular signaling molecules, among others, are regulated by cocaine via the D1 receptor, and these AP-1 transcription complex-regulated genes might contribute to persistent cocaine-induced behavioral changes.

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Identification of PSD-95 as a Regulator of Dopamine-Mediated Synaptic and Behavioral Plasticity

Cited by 346 publications

References 83 publications

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Dopaminergic signaling in dendritic spines

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

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