Impaired synaptic scaling in mouse hippocampal neurones expressing NMDA receptors with reduced calcium permeability.
NMDA receptors (NMDARs) play a crucial role for the acquisition of functional AMPARs during Hebbian synaptic plasticity at cortical and hippocampal synapses over a short timescale of seconds to minutes. In contrast, homeostatic synaptic plasticity can occur over longer timescales of hours to days. The induction mechanisms of this activity-dependent synaptic scaling are poorly understood but are assumed to be independent of NMDAR signalling in the cortex. Here we investigated in the hippocampus a potential role of NMDAR-mediated Ca(2+) influx for synaptic scaling of AMPA currents by genetic means. The Ca(2+) permeability of NMDARs was reduced by selective postnatal expression in principal neurones of mouse forebrain half of the NR1 subunits with an amino acid substitution at the critical channel site (N598R). This genetic manipulation did not reduce the total charge transfer via NMDARs in nucleated patches (somatic) and at synaptic sites. In contrast, the current amplitude and the charge carried through AMPARs were substantially reduced at somatic and synaptic sites in juvenile and adult mutants, indicating persistent downscaling of AMPA responses. Smaller and less frequent AMPA miniature currents in the mutant demonstrated a postsynaptic locus of this down-regulation. Afferent innervation and release probability were unchanged at CA3-to-CA1 synapses of mutants, as judged from input-output and minimal stimulation experiments. Our results indicate that NMDAR-mediated Ca(2+) signalling is important for synaptic scaling of AMPA currents in the hippocampus in vivo.
Pawlak
Verena
V
Department of Molecular Neurobiology, Max-Planck-Institute for Medical Research, Jahnstrasse 29, D-69120 Heidelberg, Germany.
Schupp
Bettina J
BJ
Single
Frank N
FN
Seeburg
Peter H
PH
Köhr
Georg
G
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000502:physiology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D002118:Calcium