title: Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal.
abstract: At glutamatergic synapses, both long-term potentiation (LTP) and long-term depression (LTD) can be induced at the same synaptic activation frequency. Instructive signals determine whether LTP or LTD is induced, by modulating local calcium transients. Synapses maintain the ability to potentiate or depress over a wide frequency range, but it remains unknown how calcium-controlled plasticity operates when frequency variations alone cause differences in calcium amplitudes. We addressed this problem at cerebellar parallel fiber-Purkinje cell synapses, which can undergo LTD or LTP in response to 1-Hz and 100-Hz stimulation. We observed that high-frequency activation elicits larger spine calcium transients than low-frequency stimulation under all stimulus conditions, but, regardless of activation frequency, climbing fiber (CF) coactivation provides an instructive signal that further enhances calcium transients and promotes LTD. At both frequencies, buffering calcium prevents LTD induction and LTP results instead, identifying the enhanced calcium signal amplitude as the critical parameter contributed by the instructive CF signal. These observations show that it is not absolute calcium amplitudes that determine whether LTD or LTP is evoked but, instead, the LTD threshold slides, thus preserving the requirement for relatively larger calcium transients for LTD than for LTP induction at any given stimulus frequency. Cerebellar LTD depends on the activation of calcium/calmodulin-dependent kinase II (CaMKII). Using genetically modified (TT305/6VA and T305D) mice, we identified α-CaMKII inhibition upon autophosphorylation at Thr305/306 as a molecular event underlying the threshold shift. This mechanism enables frequency-independent plasticity control by the instructive CF signal based on relative, not absolute, calcium thresholds.
authors: Department of Neurobiology, University of Chicago, Chicago, IL 60637.
authors: Claire
authors: C
authors: Piochon
authors: Department of Neurobiology, University of Chicago, Chicago, IL 60637.
authors: Heather K
authors: HK
authors: Titley
authors: Department of Neurobiology, University of Chicago, Chicago, IL 60637.
authors: Dana H
authors: 0000-0003-4852-4703
authors: DH
authors: Simmons
authors: Department of Neurobiology, University of Chicago, Chicago, IL 60637.
authors: Giorgio
authors: 0000-0002-2942-9615
authors: G
authors: Grasselli
authors: Department of Neuroscience, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors: Ype
authors: Y
authors: Elgersma
authors: Department of Neurobiology, University of Chicago, Chicago, IL 60637; chansel@bsd.uchicago.edu.
authors: Christian
authors: C
authors: Hansel
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000502:physiology*; D011689:Purkinje Cells / Q000502:physiology*; D013569:Synapses / Q000502:physiology
chemical_list: D002118:Calcium
keywords: Purkinje cell; calcium/calmodulin-dependent kinase II; cerebellum; long-term depression; long-term potentiation