Jill Rocchetti1, Elsa Isingrini1, Gregory Dal Bo1, Sara Sagheby1, Aurore Menegaux1, François Tronche2, Daniel Levesque3, Luc Moquin1, Alain Gratton1, Tak Pan Wong1, Marcelo Rubinstein4, Bruno Giros5. 1. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada. 2. Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche en Santé 1130, and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8246, Sorbonne University Université Pierre et Marie Curie, Neuroscience Paris Seine, Paris, France. 3. Département de Pharmacie, Université de Montréal, Montreal, Quebec, Canada. 4. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Instituto de Investigaciones en Ingenieria Genética y Biologia Molecular (CONICET), Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina. and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina. 5. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada; Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche en Santé 1130, and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8246, Sorbonne University Université Pierre et Marie Curie, Neuroscience Paris Seine, Paris, France. Electronic address: bruno.giros@mcgill.ca.
Abstract
BACKGROUND: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. METHODS: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. RESULTS: Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. CONCLUSIONS: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders.
BACKGROUND: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. METHODS: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. RESULTS:Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. CONCLUSIONS: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders.
Authors: E P Bello; R Casas-Cordero; G L Galiñanes; E Casey; M A Belluscio; V Rodríguez; D Noaín; M G Murer; M Rubinstein Journal: Mol Psychiatry Date: 2016-07-19 Impact factor: 15.992
Authors: Donald C Goff; Botao Zeng; Babak A Ardekani; Erica D Diminich; Yingying Tang; Xiaoduo Fan; Isaac Galatzer-Levy; Chenxiang Li; Andrea B Troxel; Jijun Wang Journal: JAMA Psychiatry Date: 2018-04-01 Impact factor: 21.596
Authors: Lars Nyberg; Nina Karalija; Alireza Salami; Micael Andersson; Anders Wåhlin; Neda Kaboovand; Ylva Köhncke; Jan Axelsson; Anna Rieckmann; Goran Papenberg; Douglas D Garrett; Katrine Riklund; Martin Lövdén; Ulman Lindenberger; Lars Bäckman Journal: Proc Natl Acad Sci U S A Date: 2016-06-23 Impact factor: 11.205