Abstract

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. Ca²⁺ ions serve as a canonical regulator of LTP/LTD but little is known about the effect of acetylcholine on intracellular Ca²⁺ dynamics. Here, we investigated dendritic Ca²⁺ 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 ∼20 mV EPSP, applied via a glass electrode located ∼10 μm from the basal dendrite, evoked NMDA receptor-dependent fast Ca²⁺ transients and the subsequent Ca²⁺ release from the inositol 1,4,5-trisphosphate (IP₃)-sensitive stores. These secondary dendritic Ca²⁺ transients were highly localized within 10 μm from the center (SD = 5.0 μm). The dendritic release of Ca²⁺ was a prerequisite for input-specific muscarinic LTP (LTPm). Without the secondary Ca²⁺ release, only muscarinic LTD (LTDm) was induced. D(−)-2-amino-5-phosphopentanoic acid and intracellular heparin blocked LTPm as well as dendritic Ca²⁺ release. A single burst consisting of 3 EPSPs with weak stimulus intensities instead of the SES also induced secondary Ca²⁺ 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 IP₃-dependent Ca²⁺ release.