Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse...

Area of Science:

• Neuroscience
• Cellular Physiology
• Epilepsy Research

Background:

• Extracellular potassium concentration ([K+]o) significantly impacts neuronal excitability.
• Astrocytes are hypothesized to regulate [K+]o via Connexin-43 (Cx43)-based Gap Junctions (GJs).
• The precise role of astrocytic GJs in seizure generation remains unclear.

Purpose of the Study:

• To investigate the in vivo role of astrocytic GJs and hemichannels in regulating extracellular potassium ([K+]o).
• To determine if elevated [K+]o alone triggers seizure activity.
• To differentiate the functions of GJ versus hemichannel activity in [K+]o buffering.

Main Methods:

• In vivo measurement of cortical extracellular potassium ([K+]o) using microelectrodes.
• Administration of GJ and hemichannel blockers (CBX, Gap27, TAT-Gap19) and a convulsant (4-aminopyridine).
• Assessment of neuronal excitability via local field potential (LFP) responses and resting state activity.

Main Results:

• Blocking Cx43 GJs/hemichannels with Gap27 significantly increased [K+]o (from 1.9±0.7 to 9±1mM) without inducing seizures.
• Broad connexin channel blockade (CBX) also elevated [K+]o (to 11±3mM), but seizures were not observed.
• 4-aminopyridine induced seizures and increased [K+]o to ~10mM, while direct K+ application did not trigger seizures.

Conclusions:

• Astrocytic GJs are critical for in vivo spatial buffering of extracellular potassium ([K+]o).
• Elevated [K+]o alone is insufficient to trigger neocortical seizures.
• Cx43 hemichannel blockade had a minimal effect on [K+]o regulation compared to GJ blockade.