title: NMDA receptors with incomplete Mg²⁺ block enable low-frequency transmission through the cerebellar cortex.
abstract: The cerebellar cortex coordinates movements and maintains balance by modifying motor commands as a function of sensory-motor context, which is encoded by mossy fiber (MF) activity. MFs exhibit a wide range of activity, from brief precisely timed high-frequency bursts, which encode discrete variables such as whisker stimulation, to low-frequency sustained rate-coded modulation, which encodes continuous variables such as head velocity. While high-frequency MF inputs have been shown to activate granule cells (GCs) effectively, much less is known about sustained low-frequency signaling through the GC layer, which is impeded by a hyperpolarized resting potential and strong GABA(A)-mediated tonic inhibition of GCs. Here we have exploited the intrinsic MF network of unipolar brush cells to activate GCs with sustained low-frequency asynchronous MF inputs in rat cerebellar slices. We find that low-frequency MF input modulates the intrinsic firing of Purkinje cells, and that this signal transmission through the GC layer requires synaptic activation of Mg²⁺-block-resistant NMDA receptors (NMDARs) that are likely to contain the GluN2C subunit. Slow NMDAR conductances sum temporally to contribute approximately half the MF-GC synaptic charge at hyperpolarized potentials. Simulations of synaptic integration in GCs show that the NMDAR and slow spillover-activated AMPA receptor (AMPAR) components depolarize GCs to a similar extent. Moreover, their combined depolarizing effect enables the fast quantal AMPAR component to trigger action potentials at low MF input frequencies. Our results suggest that the weak Mg²⁺ block of GluN2C-containing NMDARs enables transmission of low-frequency MF signals through the input layer of the cerebellar cortex.
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, F-75005 France.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Schwartz
authors.forename: Jason S
authors.initials: JS
authors.lastname: Rothman
authors.forename: Guillaume P
authors.initials: GP
authors.lastname: Dugué
authors.forename: Marco
authors.initials: M
authors.lastname: Diana
authors.forename: Charly
authors.initials: C
authors.lastname: Rousseau
authors.forename: R Angus
authors.initials: RA
authors.lastname: Silver
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dieudonné
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002525:Cerebellar Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000502:physiology; D011689:Purkinje Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012118:Resorcinols; C079215:3,5-dihydroxyphenylglycine; D008274:Magnesium; D005998:Glycine