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Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13602-13610. doi: 10.1073/pnas.1816013116. Epub 2019 May 31.

Circuit-specific control of the medial entorhinal inputs to the dentate gyrus by atypical presynaptic NMDARs activated by astrocytes.

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Département de Neurosciences Fondamentales, Université de Lausanne, 1005 Lausanne, Switzerland.
Synaptic Structure Laboratory, Instituto de Investigación en Discapacidades Neurológicas, Departamento Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02071 Albacete, Spain.
Département de Neurosciences Fondamentales, Université de Lausanne, 1005 Lausanne, Switzerland;


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.


GluN3a; NMDAR; astrocyte; plasticity; presynaptic

Conflict of interest statement

The authors declare no conflict of interest.

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