Adenosine A1 receptor activation mediates the developmental shift at layer 5 pyramidal cell synapses and is a determinant of mature synaptic strength

Michael I Kerr,Mark J Wall,Magnus J E Richardson

doi:10.1113/jphysiol.2012.244392

Abstract

During the first postnatal month glutamatergic synapses between layer 5 pyramidal cells in the rodent neocortex switch from an immature state exhibiting a high probability of neurotransmitter release, large unitary amplitude and synaptic depression to a mature state with decreased probability of release, smaller unitary amplitude and synaptic facilitation. Using paired recordings, we demonstrate that the developmental shift in release probability at synapses between rat somatosensory layer 5 thick-tufted pyramidal cells is mediated by a higher and more heterogeneous activation of presynaptic adenosine A1 receptors. Immature synapses under control conditions exhibited distributions of coefficient of variation, failure rate and release probability that were almost coincident with the A1 receptor blocked condition; however, mature synapses under control conditions exhibited much broader distributions that spanned those of both the A1 receptor agonized and antagonized conditions. Immature and mature synapses expressed A1 receptors with no observable difference in functional efficacy and therefore the heterogeneous A1 receptor activation seen in the mature neocortex appears due to increased adenosine concentrations that vary between synapses. Given the central role demonstrated for A1 receptor activation in determining synaptic amplitude and the statistics of transmission between mature layer 5 pyramidal cells, the emplacement of adenosine sources and sinks near the synaptic terminal could constitute a novel form of long-term synaptic plasticity.

Highlights

Many cortical glutamatergic synapses exhibit a developmental reduction in the probability of neurotransmitter release (Feldmeyer & Radnikow, 2009)
We examined the characteristics of synaptic transmission between layer 5 pyramidal cell (L5PC) in the immature (P17–P22) and the mature (P27–P32) somatosensory cortex under various conditions of A1 receptor (A1R) activation (Fig. 1): A1R block by the antagonist 8CPT; control conditions, to measure A1R activation by endogenous
We provided evidence that increased activation of presynaptic A1Rs mediates the developmental reduction in release probability that partly underlies the reduced unitary amplitude and fully underlies the increase in variability, decrease in reliability and change in synaptic dynamics from depression to facilitation previously observed at L5PC synapses (Reyes & Sakmann, 1999; Frick et al 2007; Feldmeyer & Radnikow, 2009; Etherington & Williams, 2011)

Summary

Introduction

Many cortical glutamatergic synapses exhibit a developmental reduction in the probability of neurotransmitter release (Feldmeyer & Radnikow, 2009). Thick-tufted layer 5 pyramidal cells (L5PCs) are representative with unitary EPSP amplitudes reduced from 1.3 mV (Markram et al 1997) to 0.3 mV (Reyes & Sakmann, 1999) and short-term plasticity changing from depression to facilitation This change coincides with the period of critical plasticity in the rodent, with the onset of hearing and eye opening around the end of the second postnatal week, and contributes to the sharpened response of the neocortical microcircuit to sensory stimuli (Oswald & Reyes, 2008; Etherington & Williams, 2011). The maturation of these central excitatory synapses has been linked to processes that reduce transient calcium concentrations in the presynaptic terminal (Feldmeyer & Radnikow, 2009) but to our knowledge the specific mechanism has not been identified

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Conclusion