title: Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning.
abstract: Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABA(A)-receptor Cl(-) channels. Although Kcc2 may have a morphogenic role in synapse development, Kcc2 disruption neither changed synapse density nor spine morphology. In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl(-)](i) roughly two-fold. The reduced Cl(-) gradient nearly abolished GABA-induced hyperpolarization in PCs, but in GCs it merely affected excitability by membrane depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, whereas baseline performance, short-term gain-decrease learning and gain consolidation remained intact. These functions, however, were affected by disruption of Kcc2 in PCs. GC excitability plays a previously unknown, but specific role in consolidation of phase learning.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Seja
authors.forename: Martijn
authors.initials: M
authors.lastname: Schonewille
authors.forename: Guillermo
authors.initials: G
authors.lastname: Spitzmaul
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Badura
authors.forename: Ilse
authors.initials: I
authors.lastname: Klein
authors.forename: York
authors.initials: Y
authors.lastname: Rudhard
authors.forename: William
authors.initials: W
authors.lastname: Wisden
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D002525:Cerebellar Cortex / Q000166:cytology / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry*; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D012027:Reflex, Vestibulo-Ocular; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D027981:Symporters; D000096922:K Cl- Cotransporters