Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia.
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.
Morice
Elise
E
INSERM U513, Neurobiologie et Psychiatrie, 94010 Créteil Cedex, France.
Billard
Jean-Marie
JM
Denis
Cécile
C
Mathieu
Flavie
F
Betancur
Catalina
C
Epelbaum
Jacques
J
Giros
Bruno
B
Nosten-Bertrand
Marika
M
D000818:Animals; D001928:Brain Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D019965:Neurocognitive Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate; D006220:Haloperidol; D004298:Dopamine