TY - JOUR
T1 - Chloride cotransporters as a molecular mechanism underlying spreading depolarization-induced dendritic beading
AU - Steffensen, Annette B.
AU - Sword, Jeremy
AU - Croom, Deborah
AU - Kirov, Sergei A.
AU - MacAulay, Nanna
N1 - Publisher Copyright:
© 2015 the authors.
PY - 2015/9/2
Y1 - 2015/9/2
N2 - Spreading depolarizations (SDs) are waves of sustained neuronal and glial depolarization that propagate massive disruptions of ion gradients through the brain. SD is associated with migraine aura and recently recognized as a novel mechanism of injury in stroke and brain trauma patients. SD leads to neuronal swelling as assessed in real time with two-photon laser scanning microscopy (2PLSM). Pyramidal neurons do not express aquaporins and thus display low inherent water permeability, yet SD rapidly induces focal swelling (beading) along the dendritic shaft by unidentified molecular mechanisms. To address this issue, we induced SD in murine hippocampal slices by focal KCl microinjection and visualized the ensuing beading of dendrites expressing EGFP by 2PLSM. We confirmed that dendritic beading failed to arise during large (100 mOsm) hyposmotic challenges, underscoring that neuronal swelling does not occur as a simple osmotic event. SD-induced dendritic beading was not prevented by pharmacological interference with the cytoskeleton, supporting the notion that dendritic beading may result entirely from excessive water influx. Dendritic beading was strictly dependent on the presence of Cl-, and, accordingly, combined blockade of Cl--coupled transporters led to a significant reduction in dendritic beading without interfering with SD. Furthermore, our in vivo data showed a strong inhibition of dendritic beading during pharmacological blockage of these cotransporters. We propose that SD-induced dendritic beading takes place as a consequence of the altered driving forces and thus activity for these cotransporters, which by transport of water during their translocation mechanism may generate dendritic beading independently of osmotic forces.
AB - Spreading depolarizations (SDs) are waves of sustained neuronal and glial depolarization that propagate massive disruptions of ion gradients through the brain. SD is associated with migraine aura and recently recognized as a novel mechanism of injury in stroke and brain trauma patients. SD leads to neuronal swelling as assessed in real time with two-photon laser scanning microscopy (2PLSM). Pyramidal neurons do not express aquaporins and thus display low inherent water permeability, yet SD rapidly induces focal swelling (beading) along the dendritic shaft by unidentified molecular mechanisms. To address this issue, we induced SD in murine hippocampal slices by focal KCl microinjection and visualized the ensuing beading of dendrites expressing EGFP by 2PLSM. We confirmed that dendritic beading failed to arise during large (100 mOsm) hyposmotic challenges, underscoring that neuronal swelling does not occur as a simple osmotic event. SD-induced dendritic beading was not prevented by pharmacological interference with the cytoskeleton, supporting the notion that dendritic beading may result entirely from excessive water influx. Dendritic beading was strictly dependent on the presence of Cl-, and, accordingly, combined blockade of Cl--coupled transporters led to a significant reduction in dendritic beading without interfering with SD. Furthermore, our in vivo data showed a strong inhibition of dendritic beading during pharmacological blockage of these cotransporters. We propose that SD-induced dendritic beading takes place as a consequence of the altered driving forces and thus activity for these cotransporters, which by transport of water during their translocation mechanism may generate dendritic beading independently of osmotic forces.
KW - Cl-cotransporters
KW - Cotransporters
KW - Dendritic beading
KW - Neuronal swelling
KW - Spreading depression
KW - Two-photon microscopy
UR - http://www.scopus.com/inward/record.url?scp=84940936345&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940936345&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0400-15.2015
DO - 10.1523/JNEUROSCI.0400-15.2015
M3 - Article
C2 - 26338328
AN - SCOPUS:84940936345
SN - 0270-6474
VL - 35
SP - 12172
EP - 12187
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 35
ER -