In Rasmussen Encephalitis, Hemichannels Associated with Microglial Activation are linked to Cortical Pyramidal Neuron Coupling: A Possible Mechanism for Cellular Hyperexcitability

Abstract

Aims Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Methods Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n=16) and non-RE (n=12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Results Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye-coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases. Conclusions In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible anti-seizure treatment for RE may involve the use of gap junction blockers.

Distinct synaptic and neurochemical changes to the granule cell-CA3 projection in Bassoon mutant mice

“…Microglial cells are fine sensors of altered neuronal activity (Béchade et al, 2013 ). Indeed, a typical feature of microglia activation in response to increased neuronal activity is an up-regulation of Iba1 (Avignone et al, 2008 ; Shapiro et al, 2008 ; Wirenfeldt et al, 2009 ; Cepeda et al, 2015 ). Furthermore, detailed morphological analyses revealed that microglia exhibit larger somata and thicker proximal processes in response to general convulsion activity (Avignone et al, 2008 ).…”

Diseases associated with leaky hemichannels

“…Accordingly, blockage of HCs improved memory impairment in a mouse model of Alzheimer’s disease ( Takeuchi et al, 2011 ). Other neurodegenerative diseases in which HC have been involved are: HIV encephalitis ( Eugenin and Berman, 2013 ; Orellana et al, 2014 ), amyotrophic lateral sclerosis ( Boillee et al, 2006 ; Yamanaka et al, 2008 ; Takeuchi et al, 2011 ), Parkinson’s disease ( Rufer et al, 1996 ; Kawasaki et al, 2009 ), Rasmussen encephalitis ( Cepeda et al, 2015 ) and epilepsy ( Mylvaganam et al, 2014 ). A common milestone of these diseases is the inflammation condition, where cytokines and reactive oxygen species (ROS) can activate HCs in glial cells (astrocytes and microglia; Retamal et al, 2007 ) increasing the extracellular concentration of compounds, like ATP and glutamate, that could indirectly open Pannexin1 channels leading to neuronal death ( Orellana et al, 2012 ; Bosch and Kielian, 2014 ; Takeuchi and Suzumura, 2014 ).…”

Connexins and Pannexins: New Insights into Microglial Functions and Dysfunctions

“…Although connexin36 (Cx36) and connexin32 (Cx32) are highly expressed in the resting surveillance state (Parenti et al, 2002 ; Dobrenis et al, 2005 ; Maezawa and Jin, 2010 ), Cx43 protein and messenger ribonucleic acid (mRNA) expression is rarely detected under these conditions (Eugenín et al, 2001 ; Martínez et al, 2002 ; Rouach et al, 2002 ; Dobrenis et al, 2005 ; Garg et al, 2005 ; Hinkerohe et al, 2005 , 2010 ; Lee et al, 2005 ; Même et al, 2006 ; Shaikh et al, 2012 ; Richter et al, 2014 ). When microglia shift from resting to activated states in different pathological scenarios, connexin expression increases, particularly connexin29 (Cx29; Moon et al, 2010 ), Cx32 (Takeuchi et al, 2006 ; Maezawa and Jin, 2010 ; Moon et al, 2010 ), Cx36 (Cepeda et al, 2015 ) and Cx43 (Eugenín et al, 2001 ; Garg et al, 2005 ; Orellana et al, 2011b ; Eugenin et al, 2012 ; Sáez et al, 2013 ; Talaverón et al, 2014 ; Table 1 ). In the first study to demonstrate this phenomenon, reported by Eugenín et al ( 2001 ), stab wound injury or treatment with tumor necrosis factor alpha (TNF-α) plus interferon gamma (IFN-γ) promoted microglial activation and strongly increased Cx43 expression based on immunofluorescence and western blotting analyses.…”