Adenosine Receptor-Mediated Developmental Loss of Spike Timing-Dependent Depression in the Hippocampus.

Mikel Pérez-Rodríguez,Yuniesky Andrade-Talavera,José A Armengol,Gonzalo Flores,José Prius-Mengual,Paloma Duque-Feria,Antonio Rodríguez-Moreno,Luis E Arroyo-García,Eva M Pérez-Villegas

doi:10.1093/cercor/bhy194

Abstract

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.

Highlights

One of the most interesting properties of the mammalian brain is its ability to change in response to experience
We found that presynaptic timingdependent long-term depression (t-longterm depression (LTD)) can be induced at hippocampal CA3–CA1 synapses in young mice (P8–P21), this presynaptic form of plasticity is lost in the fourth week of development (P22–P30), and we confirmed that this form of plasticity does not require postsynaptic NMDARs
These results extend the developmental period of timing-dependent LTD reported previously for CA3–CA1 synapses in the hippocampus into young adulthood, and they extend the developmental loss of t-LTD observed in other brain regions to the hippocampus

Summary

Introduction

One of the most interesting properties of the mammalian brain is its ability to change in response to experience. Permissive and critical periods of plasticity exist during development (stages of maturation during the lifespan of organisms), windows in which intense activity (sensory)-dependent plasticity occurs and environmental experiences have the greatest impact on brain circuitry. In these windows of plasticity, the reordering and refinement of neural connections drives the formation of the definitive circuits responsible for correct adult physiology (Hensch 2005). Spike timing-dependent plasticity (STDP) is a Hebbian form of long-term synaptic plasticity detected in all species studied from insects to humans, and it is a strong candidate to underlie circuit remodeling during development, as well as for learning and memory (see Feldman 2012 for a review). Timing-dependent LTP (t-LTP) occurs when a presynaptic spike is followed by a postsynaptic spike within 10–15 ms, whereas timing-dependent LTD (t-LTD) is induced when this order is reversed (Feldman 2012)

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