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An electrophysical study of synaptic glutamate receptors in cerebellar golgi cells during development

Mok, Man Hin; (2003) An electrophysical study of synaptic glutamate receptors in cerebellar golgi cells during development. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

N-methyl-D-aspartate receptors (NMDARs) are assemblies of NR1 and NR2 (NR2A-2D) subunits and their kinetic and pharmacological properties depend on the NR2 subunits expressed. We examined developmental changes in NMDAR- mediated excitatory postsynaptic currents (EPSCs) in mouse cerebellar Golgi cells in acute thin slices. Further, we investigated whether NMDAR subtypes are differentially distributed at synaptic and extrasynaptic sites. EPSCs were recorded under whole-cell voltage-clamp. EPSC decay kinetics and pharmacology were studied at postnatal days (P)7-8 and P15-18. We found EPSCs at P7-8 to be highly sensitive to the NR2B-selective antagonist ifenprodil. At P15-18, EPSCs were shorter in duration, less ifenprodil-sensitive but more sensitive to TPEN, an agent affecting NR2A-NMDARs. Taken together, these observations suggest a developmental switch from NR2B- to NR2A-NMDARs. We next examined whether similar changes occur extrasynaptically. Extrasynaptic NMDARs, activated by a high-frequency train of stimuli, were compared with synaptic NMDARs activated by a single stimulus. Single- and trains of EPSCs at P7-8 were highly ifenprodil-sensitive, suggesting NR2B-NMDARs are present both synaptically and extrasynaptically. At P15-18, train-generated EPSCs were slower and more ifenprodil-sensitive than single EPSCs. Ifenprodil sensitivity was further increased after blockade of synaptic NMDARs with the channel-blocker MK801. This supports the idea that the NR2B-to-NR2A switch is restricted to the synapse. NR2D-containing NMDARs are present on the soma of Golgi cells. To investigate whether NR2D-NMDARs are involved in synaptic transmission, we compared EPSCs from wild-type and NR2D-ablated mice at P7-10. We found no apparent differences in EPSC properties, suggesting NR2D is restricted to extrasynaptic sites. In conclusion, cerebellar Golgi cells express several NMDAR subtypes which are differentially distributed within the cell and developmentally regulated. At P7-8, NR2B-receptors are present at and peripheral to the synapse and NR2D-receptors are in the soma. By P15-18, NR2A-NMDARs are targeted to synapses while NMDARs in the vicinity remain of the NR2B subtype.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: An electrophysical study of synaptic glutamate receptors in cerebellar golgi cells during development
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10107135
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