Adenosine A2A receptors format long-term depression and memory strategies in a mouse model of Angelman syndrome

Abstract

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_2AR) are powerful modulators of aberrant synaptic plasticity and A_2AR blockade prevents memory dysfunction in various brain diseases, we tested if A_2AR 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_2AR in the hippocampus of Ube3a^m-/p+ mice and their chronic treatment with the selective A_2AR 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_2AR as a new prospective therapeutic target to manage learning deficits in AS.

Keywords: Adenosine A(2A) receptor; Angelman syndrome; Hippocampus; Mouse model; Synaptic plasticity; Ube3a.