The Impact of Astrocytic Gap Junctional Coupling on Potassium Buffering in the Hippocampus

Abstract

Astrocytic gap junctions have been suggested to contribute to spatial buffering of potassium in the brain. Direct evidence has been difficult to gather because of the lack of astrocyte-specific gap junction blockers. We obtained mice with coupling-deficient astrocytes by crossing conditional connexin43-deficient mice with connexin30 Ϫ/Ϫ mice. Similar to wild-type astrocytes, genetically uncoupled hippocampal astrocytes displayed negative resting membrane potentials, time-and voltage-independent whole-cell currents, and typical astrocyte morphologies. Astrocyte densities were also unchanged. Using potassium-selective microelectrodes, we assessed changes in potassium buffering in hippocampal slices of mice with coupling-deficient astrocytes. We demonstrate that astrocytic gap junctions accelerate potassium clearance, limit potassium accumulation during synchronized neuronal firing, and aid in radial potassium relocation in the stratum lacunosum moleculare. Furthermore, slices of mice with coupling-deficient astrocytes displayed a reduced threshold for the generation of epileptiform events. However, it was evident that radial relocation of potassium in the stratum radiatum was not dependent on gap junctional coupling. We suggest that the perpendicular array of individual astrocytes in the stratum radiatum makes these cells ideally suited for spatial buffering of potassium released by pyramidal cells, independent of gap junctions. In general, a surprisingly large capacity for K ϩ clearance was conserved in mice with coupling-deficient astrocytes, indicating that gap junctiondependent processes only partially account for K ϩ buffering in the hippocampus.

Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

“…The importance of astrocytes and morphological contacts formed between astrocytic processes and synapses is apparent as astrocytes and astrocyte-conditioned media promote synapse formation (Pfrieger and Barres, 1997;Ullian et al, 2001) and both LTP and LTD are affected by astrocytes acting through several mechanisms. Astrocytes directly regulate NMDA-receptor-dependent LTP and plasticity through glial-derived D-serine (Yang et al, 2003;Panatier et al, 2006), ATP and adenosine (Pascual et al, 2005;Fields and Burnstock, 2006), glutamate reuptake and release (Haydon and Carmignoto, 2006) and extracellular K + handling (Wallraff et al, 2006;Djukic et al, 2007;Ge and Duan, 2007). Our findings on activity-dependent astrocyte differentiation by ATP and LIF in vitro and the observation of behavioral impairments in LIF −/− mice (Pechnick et al, 2004) and LIF over-expressing mice (Pechnick et al, 2004) suggest that LIF may be important in hippocampal development and plasticity in vivo through astrocytes.…”

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

“…Through this mechanism, astrocytes can facilitate spatial buffering of K + and spatial allocation of neurotransmitters and inter-astrocyte signalling over greater distances (Giaume et al, 1997;Hansson et al, 2000;Sontheimer et al, 1990;Wallraff et al, 2006). Therefore, the changes in Cx43, Kir channels and Aqp4 gene expression reported in this study are likely to have a significant impact on neuronal function and network activity during and after HA in the brain.…”

“…The downregulation of Cx43 observed in FACS-purified GFAP-EGFP + astrocytes was analyzed further, because of: (i) the fundamental physiological role of Cx43 as the main gap junction channel in astrocytes (Dermietzel et al, 1991;Iacobas et al, 2004); (ii) the downregulation of Cx43 also found in cortical tissue of hyperammonemic mice (present study); (iii) the clustering and apparent loss of connectivity between EGFP + astrocytes along the brain vasculature of hyperammonemic animals (present study); and (iv) the importance of Cx43 for potassium homeostasis in the brain (Kozoriz et al, 2006;Wallraff et al, 2006). In addition to Cx43 and gap junctions, potassium homeostasis is also regulated by astrocytic inward-rectifying potassium channels, which exist as Kir4.1 homodimers and Kir4.1/Kir5.1 heterodimers (Hibino et al, 2004;Kofuji et al, 2002;Kucheryavykh et al, 2007;Neusch et al, 2006).…”

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…CX43/CX30 double knockout leads to impaired potassium clearance and disrupts synaptic transmission and plasticity (Pannasch et al, 2011; Wallraff et al, 2006). CX43/CX30 double knockout also causes astrocyte endfeet edema and weakens the blood‐brain barrier (Ezan et al, 2012).…”