NMDA receptors amplify mossy fiber synaptic inputs at frequencies up to at least 750 Hz in cerebellar granule cells

Abstract

Neuronal integration of high-frequency signals is important for rapid information processing. Cerebellar mossy fiber axons (MFs) can fire action potentials (APs) at frequencies of more than one kilohertz. However, it is unclear whether and how the postsynaptic cerebellar granule cells (GCs) are able to process these high-frequency MF inputs. Here, we measured AP firing in GCs during high-frequency MF stimulation and show that GC firing frequency increased non-linearly when MF stimulation frequency was increased from 100 to 750 Hz. To investigate the mechanisms enabling such high-frequency signaling, we analyzed the role of N-methyl-d-aspartate receptors (NMDARs), which have been implicated in synaptic signaling at lower frequencies. Application of D-2-amino-5-phosphonopentanoic acid (APV), a potent inhibitor of NMDARs, strongly impaired the GC firing frequency during high-frequency MF stimulation. APV had no significant effect on single excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) evoked at 1 Hz at resting membrane potentials. However, the time course of EPSCs evoked at 1 Hz at depolarized potentials or following high-frequency MF stimulation was accelerated by APV. Thus, our results show that NMDAR-mediated currents amplify high-frequency MF inputs by prolonging the time courses of synaptic inputs, thereby causing greater synaptic summation of inputs. Hence, NMDARs support the integration of MF synaptic input at frequencies up to at least 750 Hz. Synapse 70:269-276, 2016. © 2016 Wiley Periodicals, Inc.

Electrogenic N‐methyl‐D‐aspartate receptor signaling enhances binaural responses in the adult brainstem

“…In general, these data provide further insights into the role of NMDAR‐mediated excitation in the adult mammalian sensory systems. That NMDARs can contribute to action potential generation has been shown in neuronal circuits including hippocampus (Otmakhova & Lisman, ; Grienberger et al ., ), cerebellum (Schwartz et al ., ; Baade et al ., ) retina (Poleg‐Polsky & Diamond, ) and brainstem (Wu, ; Kelly & Kidd, ; Sivaramakrishnan & Oliver, ; Pliss et al ., ; Porres et al ., ; Ammer et al ., ). However, the functional role of this electrogenic property of NMDARs is much less understood.…”

Direct and indirect pathways for heterosynaptic interaction underlying developmental synapse elimination in the mouse cerebellum

“…Since NMDARs are richly expressed in GCs during postnatal development 43 , 44 , it has been speculated that NMDARs contribute to MF to GC excitatory transmission. In cerebellar slice preparations, NMDAR-mediated currents were reported to amplify high-frequency MF inputs by prolonging the time courses of synaptic inputs, but NMDARs had no contribution to EPSPs/EPSCs in response to single MF stimulation at 1 Hz 70 . Therefore, NMDARs may contribute to CF synapse elimination by transmitting high-frequency MF inputs to GCs and enhancing PF activity.…”

Neurotransmitter content heterogeneity within an interneuron class shapes inhibitory transmission at a central synapse

“…Given the low levels of D-serine in the adult cerebellar cortex ( Wolosker et al, 1999 ; Wang and Zhu, 2003 ; Koga et al, 2017 ) and the tight control of glycine extracellular levels by glycine transporters ( Supplisson and Bergman, 1997 ), as both GlyT2 and GlyT1 are present around and inside the cerebellar glomeruli ( Zafra et al, 1995a , b ), glycine released at GoCs synapses is likely the source of co-agonist for GrCs NMDA receptors. GrCs specifically express NR2C-containing NMDA receptors ( Akazawa et al, 1994 ; Farrant et al, 1994 ; Monyer et al, 1994 ; Cathala et al, 2000 ) that are involved in the integration of MF input over long time scales ( Schwartz et al, 2012 ; Powell et al, 2015 ; Baade et al, 2016 ). This integration is greatest at low MF firing rates but can saturate at high MF firing rates.…”