Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation.
Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP-LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories.
Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Boeke J
BJ
van Beugen
Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands.
Xin
X
Qiao
Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Dana H
DH
Simmons
Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands.
Chris I
CI
De Zeeuw
Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA chansel@bsd.uchicago.edu.
Christian
C
Hansel
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D004149:Dioxoles; D018683:Excitatory Amino Acid Agents; D010880:Piperidines; D018091:Receptors, AMPA; D002118:Calcium