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Critical periods of synaptic plasticity facilitate the reordering and refining of neural connections during development, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. Presynaptic spike timing-dependent long-term depression (t-LTD) exists in the hippocampus, which depends on the activation of NMDARs and that probably fulfills a role in synaptic refinement. This t-LTD is present until the third postnatal week in mice, disappearing in the fourth week of postnatal development. We were interested in the mechanisms underlying this maturation related loss of t-LTD and we found that at CA3-CA1 synapses, presynaptic NMDA receptors (pre-NMDARs) are tonically active between P13 and P21, mediating an increase in glutamate release during this critical period of plasticity. Conversely, at the end of this critical period (P22-P30) and coinciding with the loss of t-LTD, these pre-NMDARs are no longer tonically active. Using immunogold electron microscopy, we demonstrated the existence of pre-NMDARs at Schaffer collateral synaptic boutons, where a decrease in the number of pre-NMDARs during development coincides with the loss of both tonic pre-NMDAR activation and t-LTD. Interestingly, this t-LTD can be completely recovered by antagonizing adenosine type 1 receptors (A1R), which also recovers the tonic activation of pre-NMDARs at P22-P30. By contrast, the induction of t-LTD was prevented at P13-P21 by an agonist of A1R, as was tonic pre-NMDAR activation. Furthermore, we found that the adenosine that mediated the loss of t-LTD during the fourth week of development is supplied by astrocytes. These results provide direct evidence for the mechanism that closes the window of plasticity associated with t-LTD, revealing novel events probably involved in synaptic remodeling during development.

Original publication




Journal article


Cereb Cortex

Publication Date





3266 - 3281


adenosine receptors, astrocytes, hippocampus, plasticity windows, spike timing-dependent plasticity, Action Potentials, Adenosine A1 Receptor Agonists, Animals, Animals, Newborn, Astrocytes, Bicuculline, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Excitatory Postsynaptic Potentials, GABA-A Receptor Antagonists, Glutamic Acid, Hippocampus, Immunohistochemistry, Long-Term Synaptic Depression, Mice, Microscopy, Electron, Neuronal Plasticity, Patch-Clamp Techniques, Presynaptic Terminals, Purinergic P1 Receptor Antagonists, Pyramidal Cells, Receptor, Adenosine A1, Receptors, N-Methyl-D-Aspartate, Theophylline