sr1001 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

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.

Topics: Acetylcholine; Action Potentials; Afferent Pathways; Aniline Compounds; Animals; Astrocytes; Atropine; Basal Nucleus of Meynert; Calcium Signaling; Cholinergic Agents; Chromatography, High Pressure Liquid; Evoked Potentials, Somatosensory; Excitatory Amino Acid Antagonists; Fluoresceins; Inositol 1,4,5-Trisphosphate Receptors; Male; Mice; Mice, Knockout; Microdialysis; Muscarinic Antagonists; Nerve Growth Factors; Neuronal Plasticity; Neurons; Physical Stimulation; Piperazines; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Serine; Somatosensory Cortex; Sulfonamides; Thiazoles; Vibrissae