Adenosine A 2A receptors format long-term depression and memory strategies in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally inherited Ube3a neuronal protein, whose main features comprise severe intellectual disabilities and motor impairments. Previous studies with the Ube3a ^m-/p+ mouse model of AS revealed deficits in synaptic plasticity and memory. Since adenosine A _2A receptors (A _2A R) are powerful modulators of aberrant synaptic plasticity and A _2A R blockade prevents memory dysfunction in various brain diseases, we tested if A _2A R could control deficits of memory and hippocampal synaptic plasticity in AS. We observed that Ube3a ^m-/p+ mice were unable to resort to hippocampal-dependent search strategies when tested for learning and memory in the Morris water maze; this was associated with a decreased magnitude of long-term depression (LTD) in CA1 hippocampal circuits. There was an increased density of A _2A R in the hippocampus of Ube3a ^m-/p+ mice and their chronic treatment with the selective A _2A R antagonist SCH58261 (0.1 mg/kg/day, ip) restored both hippocampal-dependent learning strategies, as well as LTD deficits. Altogether, this study provides the first evidence of a role of A _2A R as a new prospective therapeutic target to manage learning deficits in AS.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)