Asc-1 transporter activation: an alternative to rescue age-related alterations in functional plasticity at rat hippocampal CA3/CA1 synapses.

Activation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDA-R) represents a key functional process for memory formation. A decreased synthesis of the NMDA-R co-agonist d-serine was recently proposed to contribute to alterations of hippocampus-dependent memory mechanisms with ageing. Nevertheless, other pathways could also be involved and thus considered to be targets of interest to prevent cognitive ageing. Herein, we demonstrate that the Asc-1 subtype of neutral amino acid (nAA) transporters that regulates d-serine and glycine release from neurons could be viewed as one of these targets. At CA3/CA1 hippocampal synapses, Asc-1 activation did not modify basal glutamate neurotransmission either in adult or aged rats. In contrast, Asc-1 activation significantly increased NMDA-R-dependent long-term potentiation (LTP) in both groups of animals and fully rescued the age-related LTP deficits. This rescue in aged animals was observed only when Asc-1 activation was selectively managed by d-Isoleucine (d-Ile), but not when less specifically driven by a mixture of nAA. Similarly, while any activation of Asc-1 improved the isolated NMDA-R-induced synaptic potentials in adult rats, only d-Ile was efficient in aged animals. Taken together, these results strengthen the interest in specifically targeting Asc-1 transporters to better cure age-associated memory decline. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.