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Circuit-specific changes in d-serine-dependent activation of the N-methyl-D-aspartate receptor in the aging hippocampus

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Abstract

Age-related memory deficits have recently been associated with the impaired expression of d-serine-dependent synaptic plasticity in neuronal networks of the hippocampal CA1 area. However, whether such functional alterations are common to the entire hippocampus during aging remains unknown. Here, we found that d-serine was also required for the induction of N-methyl-D-aspartate receptor (NMDA-R)-dependent long-term potentiation (LTP) at perforant path-granule cell synapses of the dentate gyrus. LTP as well as isolated NMDA-R synaptic potentials were impaired in slices from aged rats, but in contrast to the CA1, this defect was not reversed by exogenous d-serine. The lower activation of the glycine-binding site by the endogenous co-agonist does not therefore appear to be a critical mechanism underlying age-related deficits in NMDA-R activation in the dentate gyrus. Instead, our data highlight the role of changes in presynaptic inputs as illustrated by the weaker responsiveness of afferent glutamatergic fibers, as well as changes in postsynaptic NMDA-R density. Thus, our study indicates that although NMDA-R-dependent mechanisms driving synaptic plasticity are quite similar between hippocampal circuits, they show regional differences in their susceptibility to aging, which could hamper the development of effective therapeutic strategies aimed at reducing cognitive aging.

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Abbreviations

aCSF:

Artificial cerebrospinal fluid

dAAO :

d-amino acid oxidase

fEPSP:

Field excitatory postsynaptic potential

d-APV:

d-2-amino-5-phosphonovalerate

DsdA:

d-serine deaminase

IES :

Index of synaptic efficacy

KO:

Knockout

LTP:

Long-term potentiation

NBQX:

2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide

NMDA-R:

N-methyl-d-aspartate receptor

PFV:

Presynapic fiber volley

SR:

Serine racemase

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Acknowledgment

This manuscript was prepared with editorial help from Gap Junction (www.gap-junction.com). This work was supported by the National Institute of Health and Medical research (J-M.B) and by the Israel Science Foundation, Legancy Heritage Fund and the Allen and Jewel Prince Center for Neurodegenerative Disordres of the brain (H.W)

Conflict of interest

All authors state that they have no actual or potential conflicts of interest, including financial, personal, or other relationships with concerned people or organizations within 3 years of beginning the work reported here.

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Authors and Affiliations

  1. Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, UMR 894, Paris, 75014, France

    M. Labarrière, F. Thomas, P. Dutar & J.-M. Billard

  2. Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell’Insubria, via J.H. Dunant 3, 21100, Varese, Italy

    L. Pollegioni

  3. The Protein Factory, Centro Interuniversitario di Biotecnologie Proteiche, Politecnico di Milano, ICRM CNR Milano, and Università degli Studi dell’Insubria, via Mancinelli 7, 20137, Milano, Italy

    L. Pollegioni

  4. Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31036, Israel

    H. Wolosker

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  1. M. Labarrière
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  2. F. Thomas
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  3. P. Dutar
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  4. L. Pollegioni
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  6. J.-M. Billard
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Corresponding author

Correspondence to J.-M. Billard.

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Figure S1

Basal synaptic transmission is not affected by pharmacological and enzymatic manipulations of the slices. (A) Plot of the mean non-NMDA-R-mediated synaptic efficacy (IES) determined in slices from adult rats for 300, 400 and 500μA stimulus intensities before and after application of the specific antagonist of the NMDA-R glycine binding site L689,560 (10 μM). (B) Plot of the mean IES determined in control slices and in slices pretreated with the d-serine degrading enzyme d-amino acid oxidase (dAAO). (C) Plot of the mean IES determined in control slices and in slices pretreated with the degrading enzyme d-serine deaminase (DsdA). In each condition are presented superimposed samples traces of evoked non-NMDA-R-mediated fEPSPs recorded in control condition and in the presence of the drug using a 400μA current intensity. (GIF 93 kb)

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Labarrière, M., Thomas, F., Dutar, P. et al. Circuit-specific changes in d-serine-dependent activation of the N-methyl-D-aspartate receptor in the aging hippocampus. AGE 36, 9698 (2014). https://doi.org/10.1007/s11357-014-9698-0

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