P2Y1 receptor inhibition rescues impaired synaptic plasticity and astroglial Ca2+-dependent activity in the epileptic hippocampus

NEUROBIOLOGY OF DISEASE

卷:146

Article

Martorell, Andres^1,3  Wellmann, Mario^1,2  Guiffa, Felipe¹  Fuenzalida, Marco¹  Bonansco, Christian¹ 

[1] Univ Valparaiso, Fac Ciencias, Ctr Neurobiol Fisiopatol Integrat CENFI, Inst Fisiol, Valparaiso, Chile

[2] Univ Valparaiso, Fac Med, Escuela Fonoaudiol, Valparaiso, Chile

[3] Univ Andres Bello, Fac Ciencias Rehabil, Escuela Fonoaudiol, Vina Del Mar, Chile

关键词: Gliotransmission;    Synaptic plasticity;    Epilepsy;    Astrocytes;    Purinergic receptors;    Long-term potentiation;    Kindling;   

DOI  :  10.1016/j.nbd.2020.105132

来源: Elsevier

【 摘 要 】

Epilepsy is characterized by a progressive predisposition to suffer seizures due to neuronal hyperexcitability, and one of its most common co-morbidities is cognitive decline. In animal models of chronic epilepsy, such as kindling, electrically induced seizures impair long-term potentiation (LTP), deteriorating learning and memory performance. Astrocytes are known to actively modulate synaptic plasticity and neuronal excitability through Ca2+-dependent gliotransmitter release. It is unclear, however, if astroglial Ca2+ signaling could contribute to the development of synaptic plasticity alterations in the epileptic hippocampus. By employing electrophysiological tools and Ca2+ imaging, we found that glutamatergic CA3-CA1 synapses from kindled rats exhibit an impairment in theta burst (TBS) and high frequency stimulation (HFS)-induced LTP, which is accompanied by an increased probability of neurotransmitter release (Pr) and an abnormal pattern of astroglial Ca2+-dependent transients. Both the impairment in LTP and the Pr were reversed by inhibiting purinergic P2Y1 receptors (P2Y1R) with the specific antagonist MRS2179, which also restored the spontaneous and TBS-induced pattern of astroglial Ca2+-dependent signals. Two consecutive, spaced TBS protocols also failed to induce LTP in the kindled group, however, this impairment was reversed and a strong LTP was induced when the second TBS was applied in the presence of MRS2179, suggesting that the mechanisms underlying the alterations in TBS-induced LTP are likely associated with an aberrant modulation of the induction threshold for LTP. Altogether, these results indicate that P2Y1R inhibition rescues both the pattern of astroglial Ca2+-activity and the plastic properties of CA3-CA1 synapses in the epileptic hippocampus, suggesting that astrocytes might take part in the mechanisms that deteriorate synaptic plasticity and thus cause cognitive decline in epileptic patients.