Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex

Pascal Fossat, Fabrice R. Turpin, Silvia Sacchi, Jérôme Dulong, Ting Shi, Jean-Michel Rivet, Jonathan V. Sweedler, Loredano Pollegioni, Mark J. Millan, Stéphane H.R. Oliet, Jean-Pierre Mothet
Cerebral Cortex. 2011-06-20; 22(3): 595-606
DOI: 10.1093/cercor/bhr130

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1. Cereb Cortex. 2012 Mar;22(3):595-606. doi: 10.1093/cercor/bhr130. Epub 2011 Jun
20.

Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex.

Fossat P(1), Turpin FR, Sacchi S, Dulong J, Shi T, Rivet JM, Sweedler JV,
Pollegioni L, Millan MJ, Oliet SH, Mothet JP.

Author information:
(1)Institut National de la Santé et de la Recherche Médicale U862, Neurocentre
Magendie, 33077 Bordeaux, France.

N-methyl-D-aspartate receptors (NMDARs) subserve numerous neurophysiological and
neuropathological processes in the cerebral cortex. Their activation requires the
binding of glutamate and also of a coagonist. Whereas glycine and D-serine
(D-ser) are candidates for such a role at central synapses, the nature of the
coagonist in cerebral cortex remains unknown. We first show that the
glycine-binding site of NMDARs is not saturated in acute slices preparations of
medial prefrontal cortex (mPFC). Using enzymes that selectively degrade either
D-ser or glycine, we demonstrate that under the present conditions, D-ser is the
principle endogenous coagonist of synaptic NMDARs at mature excitatory synapses
in layers V/VI of mPFC where it is essential for long-term potentiation (LTP)
induction. Furthermore, blocking the activity of glia with the metabolic
inhibitor, fluoroacetate, impairs NMDAR-mediated synaptic transmission and
prevents LTP induction by reducing the extracellular levels of D-serine. Such
deficits can be restored by exogenous D-ser, indicating that the D-amino acid
mainly originates from glia in the mPFC, as further confirmed by
double-immunostaining studies for D-ser and anti-glial fibrillary acidic protein.
Our findings suggest that D-ser modulates neuronal networks in the cerebral
cortex by gating the activity of NMDARs and that altering its levels is relevant
to the induction and potentially treatment of psychiatric and neurological
disorders.

DOI: 10.1093/cercor/bhr130
PMID: 21690263 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus