1. ¹INSERM U513, Neurobiologie et Psychiatrie, Créteil Cedex, France
2. ²INSERM U549, Neurobiologie de la Croissance et de la Sénescence, IFR Broca Sainte-Anne, Paris, France

Correspondence: Dr M Nosten-Bertrand, INSERM U513, Neurobiologie et Psychiatrie, 8 rue du Général Sarrail, 94010 Créteil Cedex, France. Tel: +33 1 49 81 35 16; Fax: +33 1 49 81 36 85; E-mail: nosten@creteil.inserm.fr

Received 25 July 2006; Revised 10 January 2007; Accepted 10 January 2007; Published online 7 March 2007.

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.