title: Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo.
abstract: Global brain state dynamics regulate plasticity in local cortical circuits, but the underlying cellular and molecular mechanisms are unclear. Here, we demonstrate that astrocyte Ca(2+) signaling provides a critical bridge between cholinergic activation, associated with attention and vigilance states, and somatosensory plasticity in mouse barrel cortex in vivo. We investigated first whether a combined stimulation of mouse whiskers and the nucleus basalis of Meynert (NBM), the principal source of cholinergic innervation to the cortex, leads to enhanced whisker-evoked local field potential. This plasticity is dependent on muscarinic acetylcholine receptors (mAChR) and N-methyl-d-aspartic acid receptors (NMDARs). During the induction of this synaptic plasticity, we find that astrocytic [Ca(2+)](i) is pronouncedly elevated, which is blocked by mAChR antagonists. The elevation of astrocytic [Ca(2+)](i) is crucial in this type of synaptic plasticity, as the plasticity could not be induced in inositol-1,4,5-trisphosphate receptor type 2 knock-out (IP(3)R2-KO) mice, in which astrocytic [Ca(2+)](i) surges are diminished. Moreover, NBM stimulation led to a significant increase in the extracellular concentration of the NMDAR coagonist d-serine in wild-type mice when compared to IP(3)R2-KO mice. Finally, plasticity in IP(3)R2-KO mice could be rescued by externally supplying d-serine. Our data present coherent lines of in vivo evidence for astrocytic involvement in cortical plasticity. These findings suggest an unexpected role of astrocytes as a gate for cholinergic plasticity in the cortex.
authors.affiliation: Laboratory for Neuron Glia Circuit and Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Takata
authors.forename: Tsuneko
authors.initials: T
authors.lastname: Mishima
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Terumi
authors.initials: T
authors.lastname: Nagai
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ebisui
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirase
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000344:Afferent Pathways / Q000502:physiology; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001285:Atropine / Q000494:pharmacology; D020532:Basal Nucleus of Meynert / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018678:Cholinergic Agents / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010812:Physical Stimulation; D010879:Piperazines / Q000494:pharmacology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D012694:Serine / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014738:Vibrissae / Q000294:innervation
chemical_list: D000814:Aniline Compounds; D018678:Cholinergic Agents; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018727:Muscarinic Antagonists; D009414:Nerve Growth Factors; C503942:Oregon green 488 BAPTA-1; D010879:Piperazines; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C558809:SR1001; D013449:Sulfonamides; D013844:Thiazoles; D012694:Serine; D001285:Atropine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D000109:Acetylcholine