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Title: The role of NMDA receptors and BDNF in learning and memory
Author: Belsham, Ashley A. G.
ISNI:       0000 0004 2682 9925
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2008
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Long-term memory formation involves biochemical, electrophysieal and morphological changes altering the strength of synapses. The N-methyl-D-aspartate receptor (NMDAR) is implicated in early stages of long term memory formation. NMDAR stimulation causes Ca^^ influx into the post synaptic neuron and activation of metabolic pathways. NMDARs are composed of combintations of NRl and NR2 subunits. NR2A and NR2B expression dominate in the forebrain. Enhanced neurotransmission causes (i) NMDARs comprised of NR2A subunits to be internalised and exchanged for those containing NR2B and (ii) release of brain-derived neurotrophic factor (BDNF). BDNF activates its receptor, tropomyosine kinase B (trkB) and mediates the exchange of NMDAR subtypes by phophorylation of NMDAR and AMP A (alpha-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid) receptor subunits. One-day-old chicks (Gallus domesticus) were trained using passive avoidance learning (PAL) changes in N Rl, NR2A, NR2B, BDNF and trkB mRNA expression in their forebrains was determined using radioactive in situ hybridisation and semi-quantitative RT-PCR. Induction of NR2A (in the IMM - a sensory sorting area of the brain; and the LSt, which contains connections to the IMM) and NR2B (in the MSt - which is associated with suppression of pecking behaviour) was specific to passive avoidance itself. N Rl, BDNF and trkB transcripts were indueed not only in PAL trained birds but in water trained controls. Radiolabelled Ifenprodil binding in the HA, IMM, MSt and LSt also increased following training indicating training induced insertion of NR2B containing receptors into neuronal membranes. To further confirm the role of NR2A and NR2B subunits in passive avoidance memory, NR2A antisense and Ifenprodil (an NR2B specific antagonist) were injected into the IMM and MSt of trained chicks and were seen to cause amnesia. Injections of K252a (which inhibits kinases associated with trkB activation) into these regions also caused amnesia suggesting memory formation was in addition dependent on trkB activation in these regions. Significant increases in BDNF expression in the nucleus rotundus (ROT), a caudal forebrain region, the role of which in passive avoidance have not yet been established, led to the sequencing of a previously unknown chick BDNF 5'-UTR. In situ hybridisation studies however, revealed that increases in total BDNF expression cannot be attributed to this 5'-UTR but to another unsequenced promoter region. Finally, the close association bewtween NMDAR and BDNF/trkB complexes and their roles in the regulation of NR2A and NR2B transcripts was also confirmed using in vitro isolated cortical slice suspensions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available