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

Lubec, Jana;Kalaba, Predrag;Hussein, Ahmed M;Feyissa, Daniel Daba;Kotob, Mohamed H;Mahmmoud, Rasha R;Wieder, Oliver;Garon, Arthur;Sagheddu, Claudia;Ilic, Marija;Dragačević, Vladimir;Cybulska-Klosowicz, Anita;Zehl, Martin;Wackerlig, Judith;Sartori, Simone B;Ebner, Karl;Kouhnavardi, Shima;Roller, Alexander;Gajic, Natalie;Pistis, Marco;Singewald, Nicolas;Leban, Johann Jakob;Korz, Volker;Malikovic, Jovana;Plasenzotti, Roberto;Sitte, Harald H;Monje, Francisco J;Langer, Thierry;Urban, Ernst;Pifl, Christian;Lubec, Gert

2021-01-01

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Abstract

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.