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Properties of NMDA receptors in identified cerebellar cell types

Misra, Charu; (1999) Properties of NMDA receptors in identified cerebellar cell types. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The pharmacological and biophysical properties of native NMDA receptors were studied using patch-clamp methods. The NMDA receptor subtypes present in cerebellar Golgi cells were investigated. Golgi cells express two distinct types of NMDA receptors in their extrasynaptic membrane. The high-conductance single-channel openings (50pS main- and 40pS sub-conductance) were inhibited in the presence of the NR2B subunit-selective antagonist ifenprodil, consistent with the presence of an NR2B-containing NMDA receptor population. These high-conductance openings were not potentiated in the presence of the zinc chelator TPEN, suggesting the absence of NR2A-containing NMDA receptors. Golgi cells also contain low-conductance NMDA receptors (39pS and 19pS) which exhibit asymmetry of transitions between the main- and sub-conductance states. Thus, ~63% of all low-conductance transitions were from the 39pS state to the 19pS state, typical of NR2D-containing NMDA receptors. The properties of both spontaneous synaptic currents, arising from a number of different inputs onto Golgi cells and evoked synaptic currents, arising from parallel fibre inputs onto Golgi cells, were similar. In both cases, the majority of the synaptic NMDA receptor current was suppressed in the presence of ifenprodil. However, a small residual NMDA receptor current remained in the presence of ifenprodil. In order to investigate the possible contribution of NR2D-containing NMDA receptors to this residual current, the decay time constant of this current was compared to that of the native NR2D-containing NMDA receptor population found in the somatic membrane of cerebellar Purkinje cells. Fast concentration jump experiments indicated that the decay of native NR2D-containing receptors was slow, ~3-4 seconds, unlike the relatively fast decay of the residual current observed at Golgi cell synapses. This suggested that NR2D-containing NMDA receptors were not present at Golgi cell synapses. The effect of TPEN was also investigated on Golgi cell synaptic currents. No evidence was obtained for the presence of NR2A-containing NMDA receptors at Golgi cell synapses. The pharmacological approaches used to examine NMDA receptors in Golgi cells were also applied to cerebellar granule cells - a developmental switch in NR2 subunit expression has been described previously in these cells. Using this pharmacological approach, I was able to demonstrate, for the first time, the switch from NR2B- to NR2A-containing NMDA receptors in cerebellar granule cells. In conclusion, Golgi cells possess two distinct types of NMDA receptor in their extrasynaptic membrane. These are the high-conductance NR2B-containing NMDA receptors and the low-conductance NR2D-containing NMDA receptors. NMDA receptors contribute to the synaptic responses in Golgi cells. The majority of this current at the parallel-fibre to Golgi cell synapse appeared to be carried by NR2B-containing NMDA receptors. We found no evidence for the presence of synaptic NR2D-containing NMDA receptors in these cells, although it is clear they are present extrasynaptically. The physiological significance of NR2D-containing NMDA receptors remains to be resolved. However, this study also highlights the suitability of pharmacological and biophysical approaches in determining NMDA receptor diversity within the CNS.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Properties of NMDA receptors in identified cerebellar cell types
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; NMDA receptors
URI: https://discovery.ucl.ac.uk/id/eprint/10103350
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