Cholinergic induction of input-specific late-phase LTP via localized Ca ²⁺ release in the visual cortex

Acetylcholine facilitates long-term potentiation (LTP) and long-term depression (LTD), substrates of learning, memory, and sensory processing, in which acetylcholine also plays a crucial role. Ca ²⁺ ions serve as a canonical regulator of LTP/LTD but little is known about the effect of acetylcholine on intracellular Ca ²⁺ dynamics. Here, we investigated dendritic Ca ²⁺ dynamics evoked by synaptic stimulation and the resulting LTP/LTD in layer 2/3 pyramidal neurons of the rat visual cortex. Under muscarinic stimulation, single-shock electrical stimulation (SES) inducing ~20mVEPSP, applied via a glass electrode located ~10μm from the basal dendrite, evokedNMDA receptor-dependent fast Ca ²⁺ transients and the subsequent Ca ²⁺ release from the inositol 1,4,5-trisphosphate (IP3)-sensitive stores. These secondary dendritic Ca ²⁺ transients were highly localized within 10μm from the center (SD=5.0μm). The dendritic release of Ca ²⁺ was a prerequisite for input-specific muscarinic LTP (LTPm). Without the secondary Ca ²⁺ release, only muscarinic LTD (LTDm) was induced. D(-)-2-amino-5-phosphopentanoic acid and intracellular heparin blockedLTPmas well as dendritic Ca ²⁺release.Asingle burst consisting of 3 EPSPs with weak stimulus intensities instead of the SES also induced secondary Ca ²⁺ release and LTPm. LTPm and LTDm were protein synthesis-dependent. Furthermore, LTPm was confined to specific dendritic compartments and not inducible in distal apical dendrites. Thus, cholinergic activation facilitated selectively compartment-specific induction of late-phase LTP through IP ₃-dependent Ca ²⁺ release.