Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia.

Full Abstract

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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Author information

Author/s: Morice, Elise (E); Billard, Jean-Marie (JM); Denis, Cécile (C); Mathieu, Flavie (F); Betancur, Catalina (C); Epelbaum, Jacques (J); Giros, Bruno (B); Nosten-Bertrand, Marika (M);

Affiliation: INSERM U513, Neurobiologie et Psychiatrie, 94010 Créteil Cedex, France.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology), published in United States. (Language: eng)

Reference: 2007-Oct; vol 32 (issue 10) : pp 2108-16

Dates: Created 2007/09/17; Completed 2007/11/20; Revised 2008/11/20;

PMID: 17342172, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Brain Diseases, Metabolic - genetics; metabolism; physiopathology
Cognition Disorders - genetics; metabolism; physiopathology
Delirium, Dementia, Amnestic, Cognitive Disorders - genetics; metabolism; physiopathology
Disease Models, Animal
Dopamine - metabolism
Dopamine Antagonists - pharmacology
Dopamine Plasma Membrane Transport Proteins - genetics
Dopamine Uptake Inhibitors - pharmacology
Female
Haloperidol - pharmacology

Hippocampus - metabolism; physiopathology
Long-Term Potentiation - genetics
Male
Maze Learning - drug effects; physiology
Memory Disorders - genetics; metabolism; physiopathology
Methylphenidate - pharmacology
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Schizophrenia - genetics; metabolism; physiopathology

Associated Chemicals: Dopamine Antagonists (0) ; Dopamine Plasma Membrane Transport Proteins (0) ; Dopamine Uptake Inhibitors (0) ; Methylphenidate (113-45-1) ; Dopamine (51-61-6) ; Haloperidol (52-86-8)

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