Local disruption of glial adenosine homeostasis in mice associates with focal electrographic seizures: A first step in epileptogenesis?

Tianfu Li, Nikki Lytle, Jing Quan Lan, Ursula S. Sandau, Detlev Boison

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Astrogliosis and associated dysfunction of adenosine homeostasis are pathological hallmarks of the epileptic brain and thought to contribute to seizure generation in epilepsy. The authors hypothesized that astrogliosis-an early component of the epileptogenic cascade-might be linked to focal seizure onset. To isolate the contribution of astrogliosis to ictogenesis from other pathological events involved in epilepsy, the authors used a minimalistic model of epileptogenesis in mice, based on a focal onset status epilepticus triggered by intra-amygdaloid injection of kainic acid. The authors demonstrate acute neuronal cell loss restricted to the injected amygdala and ipsilateral CA3, followed 3 weeks later by focal astrogliosis and overexpression of the adenosine-metabolizing enzyme adenosine kinase (ADK). Using synchronous electroencephalographic recordings from multiple depth electrodes, the authors identify the KA-injected amygdala and ipsilateral CA3 as two independent foci for the initiation of non-synchronized electrographic subclinical seizures. Importantly, seizures remained focal and restricted to areas of ADK overexpression. However, after systemic application of a non-convulsive dose of an adenosine A 1-receptor antagonist, seizures in amygdala and CA3 immediately synchronized and spread throughout the cortex, leading to convulsive seizures. This focal seizure phenotype remained stable over at least several weeks. We conclude that astrogliosis via disruption of adenosine homeostasis per se and in the absence of any other overt pathology, is associated with the emergence of spontaneous recurrent subclinical seizures, which remain stable over space and time. A secondary event, here mimicked by brain-wide disruption of adenosine signaling, is likely required to turn pre-existing subclinical seizures into a clinical seizure phenotype.

Original languageEnglish (US)
Pages (from-to)83-95
Number of pages13
JournalGlia
Volume60
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

Keywords

  • Adenosine kinase
  • Amygdala
  • Astrogliosis
  • CA3
  • Epilepsy

Fingerprint

Dive into the research topics of 'Local disruption of glial adenosine homeostasis in mice associates with focal electrographic seizures: A first step in epileptogenesis?'. Together they form a unique fingerprint.

Cite this