Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition

Autor: Marija Ilic, Jana Lubec, Alexander Roller, Vladimir Dragačević, Jovana Malikovic, Shima Kouhnavardi, Johann Leban, Roberto Plasenzotti, Simone B. Sartori, Thierry Langer, Predrag Kalaba, Marco Pistis, Judith Wackerlig, Christian Pifl, Daniel Daba Feyissa, Martin Zehl, Karl Ebner, Nicolas Singewald, Ernst Urban, Claudia Sagheddu, Arthur Garon, Mohamed H. Kotob, Ahmed M. Hussein, Rasha Refaat Mahmmoud, Francisco J. Monje, Natalie Gajic, Anita Cybulska-Klosowicz, Oliver Wieder, Gert Lubec, Harald H. Sitte, Volker Korz
Rok vydání: 2021
Předmět:
Zdroj: Molecular Psychiatry. 26:7076-7090
ISSN: 1476-5578
1359-4184
DOI: 10.1038/s41380-021-01214-x
Popis: Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.
Databáze: OpenAIRE
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