NMDA glutamate receptors (NMDARs) on substantia nigra pars compacta (SNc) dopaminergic (DA) neurones influence action potential firing patterns, forms of synaptic plasticity and may contribute to excitotoxic neurodegeneration of DA neurones in Parkinson’s disease. NMDARs are hetero-oligomers and their functional diversity is mainly determined by NR2 (A-D) subunits. In cortical areas, NR2 subunit expression changes during critical periods of development, with NR2A subunits replacing or joining NR2B subunits at excitatory synapses. The subunit composition of functional synaptic NMDARs in midbrain DA neurones during postnatal development is not known. We have used whole-cell patch-clamp recording methods in midbrain slices (300 μm) to determine the contribution of NR2B subunits to NMDAR-mediated evoked excitatory postsynaptic currents (EPSCs) in DA neurones from rats aged postnatal day (P)6 to P22. NMDAR-mediated EPSCs, isolated pharmacologically, were observed at all ages tested (P6-P22). NMDAR-mediated EPSCs were inhibited by D-AP5 (50 μM) and showed the expected voltage-dependent sensitivity to Mg2+ ions. In order to determine whether NR2B subunits form NMDARs in SNc DA neurones, we used the non-competitive antagonist ifenprodil (3-10 μM) which preferentially inhibits NR2B subunits. NMDARs in SNc DA neurones were sensitive to 3-10 μM ifenprodil at all ages tested. There was a significant decrease in the inhibitory effect of ifenprodil (10 μM) between the first and second weeks of postnatal development (P6-P8: 72.0 ± 1.5%; n = 5; P13-15: 57.9 ± 3.8% inhibition; n=13; p<0.005). No further significant change in ifenprodil sensitivity was observed between the second and third weeks of postnatal development (P20-22: 51.8 ± 7.2% inhibition; n=9; p = 0.5). These data suggest that NR2B subunits form functional NMDARs at excitatory synapses in SNc DA neurones, and contribute to NMDAR-mediated EPSCs throughout postnatal development. However, the contribution of NR2B subunits decreases early in postnatal development, and an ifenprodil-insensitive component remains.
University College London 2006 (2006) Proc Physiol Soc 3, PC161
Poster Communications: A developmental change in functional NR2B subunit expression at glutamatergic synapses in substantia nigra pars compacta dopaminergic neurones
Shona L.C. Brothwell1, Joy L. Barber1, Alasdair J. Gibb2, Susan Jones1
1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. 2. Department of Pharmacology, University College London, London, United Kingdom.
View other abstracts by:
Where applicable, experiments conform with Society ethical requirements.