Abstracts

Rationale: Pannexin1 (Panx1) is an ATP releasing channel that plays important physio-pathological roles in various tissues, including the CNS. The first in vivo evidence that Panx1 plays a role in the maintenance of the epileptiform activity came from our group using mice with global deletion of Panx1 [Santiago et al., 2011 PLOS One 6(9):e25178]. Using the KA-seizure model in 2 weeks-old mice, we demonstrated that opening of Panx1 channels contributes to the development of status epilepticus but has no effect on seizure initiation. Because Panx1 expression is ubiquitous, we here report on the relative contribution of astrocytes and neuronal Panx1 to seizures. Methods: The KA-seizure model was used in 3 weeks-old mice with Panx1 deleted from neurons or astrocytes. Clinical scores were followed for 1-2 hours after i.p. injection of KA (20 mg/kg) after which mice were euthanized and brains removed for immunohistochemical analysis of adenosine kinase expression. Results: Using the KA-seizure model in 3 weeks-old mice with Panx1 deleted from neurons or astrocytes, we found a marked difference in the progression of seizures, such that mice lacking Panx1 in astrocytes displayed a much faster onset of forelimb clonus than did mice lacking Panx1 in neurons. Immunohistochemistry of brains of seized mice revealed increased adenosine kinase (ADK) reactivity only in mice with targeted deletion of Panx1 in astrocytes. The pre-treatment of mice with iodo-tubercidin (1.0 mg/kg), an inhibitor of ADK, delayed the onset of forelimb clonus and decreased immunoreactivity of ADK in mice lacking Panx1 in astrocytes without affecting either ADK staining or the time course of seizures induced by KA in control mice. Conclusions: Our results show that astrocyte and neuronal Panx1 differentially contribute to seizure progression and suggest that Panx1 has both excitatory and inhibitory effects on brain activity depending on the cell type where it is expressed; in astrocytes, Panx1 modulates ADK expression/function and thus alter the extracellular levels of the inhibitory modulator adenosine, while in neurons, Panx1 by releasing the ATP contribute to increase neuronal excitation. Funding: NINDS-NIH: RO1-NS092726