Retrograde adenosine/A_2Areceptor signaling facilitates excitatory synaptic transmission and seizures

Abstract

A long-term change in neurotransmitter release is a widely expressed mechanism controlling neural circuits in the mammalian brain. This presynaptic plasticity is commonly mediated by retrograde signaling whereby a messenger released from the postsynaptic neuron upon activity modifies neurotransmitter release in a long-term manner by targeting a presynaptic receptor. In the dentate gyrus (DG), the main input area of the hippocampus, granule cells (GCs) and mossy cells (MCs) form a recurrent excitatory circuit that is critically involved in DG function and epilepsy. Here, we identified adenosine/A2A receptor (A2AR) as a novel retrograde signaling system that mediates presynaptic long-term potentiation (LTP) at MC-GC synapses. Using an adenosine sensor, we found that neuronal activity triggered phasic, postsynaptic TrkB-dependent release of adenosine. Additionally, epileptic seizures released adenosine in vivo, while removing A2ARs from DG decreased seizure susceptibility. Thus, adenosine/A2AR retrograde signaling mediates presynaptic LTP that may contribute to DG-dependent learning and promote epilepsy.

Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor

“…5 A – C and 6 A – C ), a subtype known to be primarily localized at the somatodendritic region ( 38 , 39 ). A recent study identified the Ado/A 2A receptor as a retrograde signaling system that mediates presynaptic long-term potentiation on mossy cells to granule cell synapses, suggesting the potential functions of Ado as a retrograde signal ( 43 ). Given the abundance of presynaptic A 1 /A 2A receptors and Ado's known presynaptic inhibition function in distinct brain regions ( 11 , 44 , 45 ), our work suggests the somatodendritic release of Ado could serve as a retrograde modulator to feedback control presynaptic release.…”

Bidirectional modulation of synaptic transmission by insulin-like growth factor-I

“…This bidirectional action probably contributes to favor or impair the generation of associative memories impacting the barrel cortex-related behaviors. Although there is a SNARE dependent release of IGF-I from neurons ( Cao et al, 2011 ) and Botox inhibits the SNARE protein-mediated membrane fusion of endosome complexes, the application of Botox, though effective in blocking the release of IGF-I stored in endosomes, can affect other neuromodulators stored in endosomes that modulate synaptic transmission, such as BDNF ( Nasrallah et al, 2021 ), and interfere with glutamate receptor trafficking ( Pellett et al, 2015 ). Additionally, further studies are necessary to investigate whether the bidirectional modulation induced by IGF-I is maintained in older animals.…”

Image_1.tif

“…This bidirectional action probably contributes to favor or impair the generation of associative memories impacting the barrel cortex-related behaviors. Although there is a SNARE dependent release of IGF-I from neurons (Cao et al, 2011) and Botox inhibits the SNARE proteinmediated membrane fusion of endosome complexes, the application of Botox, though effective in blocking the release of IGF-I stored in endosomes, can affect other neuromodulators stored in endosomes that modulate synaptic transmission, such as BDNF (Nasrallah et al, 2021), and interfere with glutamate receptor trafficking (Pellett et al, 2015). Additionally, further studies are necessary to investigate whether the bidirectional modulation induced by IGF-I is maintained in older animals.…”