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Adenosine A_2A receptors control synaptic remodeling in the adult brain.

ABSTRACT: The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A_2A receptors (A_2AR) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A_2AR to MF sprouting. A_2AR blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A_2AR located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A_2AR to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A_2AR should be activated by extracellular ATP-derived adenosine since a similar prevention/attenuation of SE-induced hippocampal MF sprouting was observed in CD73 knockout mice. These findings demonstrate that A_2AR contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A_2AR to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A_2AR axis as a regulator of circuit remodeling in the mature brain.

SUBMITTER: Xu X

PROVIDER: S-EPMC9424208 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Adenosine A<sub>2A</sub> receptors control synaptic remodeling in the adult brain.

Xu Xinli X Beleza Rui O RO Gonçalves Francisco Q FQ Valbuena Sergio S Alçada-Morais Sofia S Gonçalves Nélio N Magalhães Joana J Rocha João M M JMM Ferreira Sofia S Figueira Ana S G ASG Lerma Juan J Cunha Rodrigo A RA Rodrigues Ricardo J RJ Marques Joana M JM

Scientific reports 20220829 1

The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A<sub>2A</sub> receptors (A<s ...[more]

PMID: 36038626

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Project description:BackgroundThe over-activation of adenosine A2A receptors (A2AR) is closely implicated in cognitive impairments of Alzheimer's disease (AD). Growing evidence shows that A2AR blockade possesses neuroprotective effects on AD. Spatial navigation impairment is an early manifestation of cognitive deficits in AD. However, whether A2AR blockade can prevent early impairments in spatial cognitive function and the underlying mechanism is still unclear.MethodsA transgenic APP/PS1 mouse model of AD amyloidosis was used in this study. Behavioral tests were conducted to observe the protective effects of A2AR blockade on early spatial memory deficits in 4-month old APP/PS1 mice. To investigate the underlying synaptic mechanism of the protective effects of A2AR blockade, we further examined long-term potentiation (LTP) and network excitation/inhibition balance of dentate gyrus (DG) region, which is relevant to unique synaptic functions of immature adult-born granule cells (abGCs). Subsequently, the protective effects of A2AR blockade on dendritic morphology and synaptic plasticity of 6-week-old abGCs was investigated using retrovirus infection and electrophysiological recordings. The molecular mechanisms underlying neuroprotective properties of A2AR blockade on the synaptic plasticity of abGCs were further explored using molecular biology methods.ResultsAPP/PS1 mice displayed DG-dependent spatial memory deficits at an early stage. Additionally, impaired LTP and an imbalance in network excitation/inhibition were observed in the DG region of APP/PS1 mice, indicating synaptic structural and functional abnormalities of abGCs. A2AR was found to be upregulated in the hippocampus of the APP/PS1 mouse model of AD. Treatment with the selective A2AR antagonist SCH58261 for three weeks significantly ameliorated spatial memory deficits in APP/PS1 mice and markedly restored LTP and network excitation/inhibition balance in the DG region. Moreover, SCH58261 treatment restored dendritic morphology complexity and enhanced synaptic plasticity of abGCs in APP/PS1 mice. Furthermore, SCH58261 treatment alleviated the impairment of synaptic plasticity in abGCs. It achieved this by remodeling the subunit composition of NMDA receptors and increasing the proportion of NR2B receptors in abGCs of APP/PS1 mice.ConclusionsBlockade of A2AR improves early spatial memory deficits in APP/PS1 mice, possibly by reversing synaptic defects of abGCs. This finding suggests that A2AR blockade could be a potential therapy for AD.

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Adenosine A_2A receptors control synaptic remodeling in the adult brain.

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Adenosine A<sub>2A</sub> receptors control synaptic remodeling in the adult brain.

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Adenosine A2A receptors control synaptic remodeling in the adult brain.

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Adenosine A&lt;sub&gt;2A&lt;/sub&gt; receptors control synaptic remodeling in the adult brain.

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OmicsDI is part of the ELIXIR infrastructure

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Adenosine A_2A receptors control synaptic remodeling in the adult brain.

Adenosine A<sub>2A</sub> receptors control synaptic remodeling in the adult brain.