title: Repeated stimulation of dopamine D1-like receptor and hyperactivation of mTOR signaling lead to generalized seizures, altered dentate gyrus plasticity, and memory deficits.
abstract: The acute activation of the dopamine D1-like receptors (D1R) is involved in a plethora of functions ranging from increased locomotor activity to the facilitation of consolidation, storage, and retrieval of memories. Although much less characterized, epileptiform activities, usually triggered by disruption of the glutamate and GABA balance, have also been reported to involve the dopaminergic transmission. Using a combination of biochemical, immunohistochemical, electrophysiological, and behavioral approaches we have investigated the consequences of repeated stimulation of D1R using the selective D1R-like agonist SKF81297. Here, we report that repeated systemic administration of SKF81297 induces kindled seizures in mice. These seizure episodes parallel the hyperactivation of the mTOR signaling in the hippocampus, leading to disrupted long-term potentiation (LTP) in the dentate gyrus (DG) and altered recognition memories. The mTOR inhibitor rapamycin delays the development of SKF81297-induced kindled seizures, and rescues LTP in the DG and object recognition. Our results show that repeated stimulation of D1R is sufficient to induce generalized seizures leading to the overactivation of mTOR signaling, disrupted hippocampal plasticity, and impaired long-term recognition memories. This work highlights the interest of mTOR inhibitors as therapeutic strategies to reverse plasticity and cognitive deficits.
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France; INSERM, U661, Montpellier, France; Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gangarossa
authors.forename: Laura
authors.initials: L
authors.lastname: Ceolin
authors.forename: Alexia
authors.initials: A
authors.lastname: Paucard
authors.forename: Mireille
authors.initials: M
authors.lastname: Lerner-Natoli
authors.forename: Julie
authors.initials: J
authors.lastname: Perroy
authors.forename: Laurent
authors.initials: L
authors.lastname: Fagni
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D018491:Dopamine Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D017447:Receptors, Dopamine D1; C067113:SK&F 81297; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus
keywords: dopamine D1R; hippocampus; mTOR signaling; memory; seizures