Hippocampal synaptic dysfunction in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis: Reversal by adenosine A2AR blockade

NEUROPHARMACOLOGY

卷:171

Article

Rei, N.^1,2  Rombo, D. M.^1,2  Ferreira, M. F.^1,2  Baqi, Y.³  Mueller, C. E.⁴  Ribeiro, J. A.^1,2  Sebastiao, A. M.^1,2  Vaz, S. H.^1,2 

[1] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon, Portugal

[2] Univ Lisbon, Fac Med, Inst Farmacol & Neurociencias, Lisbon, Portugal

[3] Sultan Qaboos Univ, Fac Sci, Dept Chem, POB 36, Muscat 123, Oman

[4] Univ Bonn, Pharmazeut Inst, Pharmazeut Chem 1, Pharma Zentrum Bonn, Bonn, Germany

关键词: ALS;    Neuronal plasticity;    Hippocampus;    Long-term potentiation (LTP);    A(2A) receptor;    KW-6002;    NMDA receptor;   

DOI  :  10.1016/j.neuropharm.2020.108106

来源: Elsevier

【 摘 要 】

Amyotrophic Lateral Sclerosis (ALS) mostly affects motor neurons, but non-motor neural and cognitive alterations have been reported in ALS mouse models and patients. Here, we evaluated if time-dependent biphasic changes in synaptic transmission and plasticity occur in hippocampal synapses of ALS SOD1(G93A) mice. Recordings were performed in hippocampal slices of SOD1(G93A )and age-matched WT mice, in the pre-symptomatic and symptomatic stages. We found an enhancement of pre-synaptic function and increased adenosine A(2A) receptor levels in the hippocampus of pre-symptomatic mice. In contrast, in symptomatic mice, there was an impairment of long-term potentiation (LTP) and a decrease in NMDA receptor-mediated synaptic currents, with A(2A)R levels also being increased. Chronic treatment with the A(2A)R antagonist KW-6002, rescued LTP and A(2A)R values. Altogether, these findings suggest an increase in synaptic function during the pre-symptomatic stage, followed by a decrease in synaptic plasticity in the symptomatic stage, which involves over-activation of A(2A)R from early disease stages.

【 授权许可】

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