Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment.
Alzheimer's disease (AD) is a neurodegenerative condition manifested by synaptic dysfunction and memory loss, but the mechanisms underlying synaptic failure are not entirely understood. Although dopamine is a key modulator of synaptic plasticity, dopaminergic neurotransmission dysfunction in AD has mostly been associated to noncognitive symptoms. Thus, we aimed to study the relationship between dopaminergic neurotransmission and synaptic plasticity in AD models. We used a transgenic model of AD (triple-transgenic mouse model of AD) and the administration of exogenous amyloid-β (Aβ) oligomers into wild type mice. We found that Aβ decreased cortical dopamine levels and converted in vivo long-term potentiation (LTP) into long-term depression (LTD) after high-frequency stimulation delivered at basolateral amygdaloid nucleus-insular cortex projection, which led to impaired recognition memory. Remarkably, increasing cortical dopamine and norepinephrine levels rescued both high-frequency stimulation -induced LTP and memory, whereas depletion of catecholaminergic levels mimicked the Aβ-induced shift from LTP to LTD. Our results suggest that Aβ-induced dopamine depletion is a core mechanism underlying the early synaptopathy and memory alterations observed in AD models and acts by modifying the threshold for the induction of cortical LTP and/or LTD.
División de Neurociencias, Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F., México.
Perla
P
Moreno-Castilla
Laboratorio de Neurobiología del Aprendizaje y la Memoria, Facultad de Psicología, División de Investigación y Estudios de Posgrado, Universidad Nacional Autónoma de México, México D.F., México.
Luis F
LF
Rodriguez-Duran
División de Neurociencias, Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F., México.
Kioko
K
Guzman-Ramos
División de Neurociencias, Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F., México.
Alejandro
A
Barcenas-Femat
Laboratorio de Neurobiología del Aprendizaje y la Memoria, Facultad de Psicología, División de Investigación y Estudios de Posgrado, Universidad Nacional Autónoma de México, México D.F., México.
Martha L
ML
Escobar
División de Neurociencias, Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F., México. Electronic address: fbermude@ifc.unam.mx.
Federico
F
Bermudez-Rattoni
D000544:Alzheimer Disease / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D009435:Synaptic Transmission / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D004298:Dopamine
Alzheimer's disease; Amyloid-beta; Dopamine; Long-term depression; Long-term potentiation; Recognition memory impairment