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

NEUROBIOLOGY OF DISEASE

卷:146

Article

Moreira-de-Sa, Ana^1,2  Goncalves, Francisco Q.¹  Lopes, Joao P.¹  Silva, Henrique B.^1,2  Tome, Angelo R.^1,3  Cunha, Rodrigo A.^1,2  Canas, Paula M.¹ 

[1] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal

[2] Univ Coimbra, Fac Med, P-3004504 Coimbra, Portugal

[3] Univ Coimbra, Fac Sci & Technol, Dept Life Sci, P-3000456 Coimbra, Portugal

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

DOI  :  10.1016/j.nbd.2020.105137

来源: Elsevier

【 摘 要 】

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.