Circuit-Specific Control of The Medial Entorhinal Inputs to The Dentate Gyrus by Atypical Presynaptic NMDARs Activated by Astrocytes

Authors

Iaroslav Savtchouk, Marquette UniversityFollow
Maria Amalia Di Castro, Université de Lausanne
Rugina Ali, Université de Lausanne
Hiltrud Stubbe, Université de Lausanne
Rafael Lujan, Universidad Castilla-La Mancha
Andrea Volterra, Université de Lausanne

Document Type

Article

Language

eng

Publication Date

7-2-2019

Publisher

National Academy of Sciences of the United States of America

Source Publication

PNAS : Proceedings of the National Academy of Sciences of the United States of America

Source ISSN

0027-8424

Abstract

Here, we investigated the properties of presynaptic N-methyl-D-aspartate receptors (pre-NMDARs) at corticohippocampal excitatory connections between perforant path (PP) afferents and dentate granule cells (GCs), a circuit involved in memory encoding and centrally affected in Alzheimer’s disease and temporal lobe epilepsy. These receptors were previously reported to increase PP release probability in response to gliotransmitters released from astrocytes. Their activation occurred even under conditions of elevated Mg²⁺ and lack of action potential firing in the axons, although how this could be accomplished was unclear. We now report that these pre-NMDARs contain the GluN3a subunit conferring them low Mg²⁺ sensitivity. GluN3a-containing NMDARs at PP-GC synapses are preponderantly presynaptic vs. postsynaptic and persist beyond the developmental period. Moreover, they are expressed selectively at medial—not lateral—PP axons and act to functionally enhance release probability specifically of the medial perforant path (MPP) input to GC dendrites. By controlling release probability, GluN3a-containing pre-NMDARs also control the dynamic range for long-term potentiation (LTP) at MPP-GC synapses, an effect requiring Ca²⁺ signaling in astrocytes. Consistent with the functional observations, GluN3a subunits in MPP terminals are localized at sites away from the presynaptic release sites, often facing astrocytes, in line with a primary role for astrocytic inputs in their activation. Overall, GluN3A-containing pre-NMDARs emerge as atypical modulators of dendritic computations in the MPP-GC memory circuit.

Comments

Accepted version. PNAS : Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 27 (July 2, 2019): 13602-13610. DOI. This article is © National Academy of Sciences of the United States of America. Used with permission.

Iaroslav Savtchouk was affiliated with Université de Lausanne at the time of publication.

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Savtchouk, Iaroslav; Di Castro, Maria Amalia; Ali, Rugina; Stubbe, Hiltrud; Lujan, Rafael; and Volterra, Andrea, "Circuit-Specific Control of The Medial Entorhinal Inputs to The Dentate Gyrus by Atypical Presynaptic NMDARs Activated by Astrocytes" (2019). Biomedical Sciences Faculty Research and Publications. 197.
https://epublications.marquette.edu/biomedsci_fac/197