Francisco Queiroz Gonçalves - CNC, University of Coimbra
Title: ACTIVATION OF NEURONAL A2AR BY ATP-DERIVED ADENOSINE FACILITATES HIPPOCAMPAL LTP: PHYSIOPATHOLOGICAL ROLE OF CD73
Abstract:
ATP is stored in synaptic vesicles and released in an activity-dependent manner. Extracellular ATP is converted to adenosine in a process mediated by ecto-nucleotidases. Ecto-5’-nucleotidase (CD73) is the rate-limiting player controlling the formation of ATP-derived adenosine (Cunha et al, 2001), which is proposed to be required for the activation of adenosine A2A receptors (A2AR) in the striatum (Augusto et al., 2013). However, in the hippocampus, where the main role of A2AR is the control of synaptic plasticity, the link between CD73 activity and A2AR function remains unclear. Here we show that, in mouse hippocampus, ATP-derived adenosine resulting from CD73 activity selectively activates A2AR to control synaptic plasticity (long term potentiation – LTP) triggered by high frequency stimulation (100 Hz, 1 s) applied to Schaffer fiber-CA1 pyramid synapses in hippocampal slices from 10 weeks-old male C57/BL6 mice. The inhibition of CD73 with α ,β -methylene ADP (AOPCP, 100 μ M) decreased LTP by 29±1.2% (n=5; P<0.05), an effect abrogated in CD73 knockout (KO) mice. The effect of AOPCP was also occluded when slices were previously superfused with the selective antagonist of A2AR (SCH58261, 50 nM). AOPCP was also devoid of effects on LTP amplitude in global A2AR-KO mice and in forebrain neuronal selective A2AR-KO mice (CAM-KII-driven A2AR-KO), whereas AOPCP significantly decreased LTP amplitude in astrocyte-selective A2AR KO mice (GFAP-driven A2AR-KO).
Intracerebroventricular administration of the neurotoxic peptide Aβ1-42 (2 nmol) induced memory related and synaptic plasticity deficits that were prevented in CD73-KO mice (n=5; P<0.05). Aβ1-42 icv injection also decreased pre- and post-synaptic protein markers in wild type but not in CD73KO mice. Overall, our results indicate that ATP-derived adenosine is strictly linked to the activation of neuronal A2AR to control synaptic plasticity in hippocampus, thus establishing CD73 as a novel target for the modulation of A2AR activity.
Title: ACTIVATION OF NEURONAL A2AR BY ATP-DERIVED ADENOSINE FACILITATES HIPPOCAMPAL LTP: PHYSIOPATHOLOGICAL ROLE OF CD73
Abstract:
ATP is stored in synaptic vesicles and released in an activity-dependent manner. Extracellular ATP is converted to adenosine in a process mediated by ecto-nucleotidases. Ecto-5’-nucleotidase (CD73) is the rate-limiting player controlling the formation of ATP-derived adenosine (Cunha et al, 2001), which is proposed to be required for the activation of adenosine A2A receptors (A2AR) in the striatum (Augusto et al., 2013). However, in the hippocampus, where the main role of A2AR is the control of synaptic plasticity, the link between CD73 activity and A2AR function remains unclear. Here we show that, in mouse hippocampus, ATP-derived adenosine resulting from CD73 activity selectively activates A2AR to control synaptic plasticity (long term potentiation – LTP) triggered by high frequency stimulation (100 Hz, 1 s) applied to Schaffer fiber-CA1 pyramid synapses in hippocampal slices from 10 weeks-old male C57/BL6 mice. The inhibition of CD73 with α ,β -methylene ADP (AOPCP, 100 μ M) decreased LTP by 29±1.2% (n=5; P<0.05), an effect abrogated in CD73 knockout (KO) mice. The effect of AOPCP was also occluded when slices were previously superfused with the selective antagonist of A2AR (SCH58261, 50 nM). AOPCP was also devoid of effects on LTP amplitude in global A2AR-KO mice and in forebrain neuronal selective A2AR-KO mice (CAM-KII-driven A2AR-KO), whereas AOPCP significantly decreased LTP amplitude in astrocyte-selective A2AR KO mice (GFAP-driven A2AR-KO).
Intracerebroventricular administration of the neurotoxic peptide Aβ1-42 (2 nmol) induced memory related and synaptic plasticity deficits that were prevented in CD73-KO mice (n=5; P<0.05). Aβ1-42 icv injection also decreased pre- and post-synaptic protein markers in wild type but not in CD73KO mice. Overall, our results indicate that ATP-derived adenosine is strictly linked to the activation of neuronal A2AR to control synaptic plasticity in hippocampus, thus establishing CD73 as a novel target for the modulation of A2AR activity.