Johnstone, Victoria Philippa Anne
Description
Long-term potentiation (LTP) in the hippocampus is a model system for investigating the mechanisms of synaptic plasticity and its role in learning and memory in the brain. Progress in understanding the mechanisms responsible for LTP has been somewhat hampered by the existence of multiple LTP variants, even at a single set of synapses. Three discrete forms of LTP (LTP1,2 and 3) that differ in their persistence and the calcium signals required for their induction have recently been characterised...[Show more] at the CA3-CA1 synapse. While the different induction mechanisms of LTP1, 2 and 3 are well characterised, it is less clear whether they are also discrete in regard to their expression and maintenance mechanisms. In this study the presynaptic expression mechanisms underlying LTP1, 2 and 3 were determined by measuring FM 1-43 destaining from CA3 terminals in hippocampal slices from male Wistar rats. No difference in vesicle turnover rate was observed for LTP1 up to 160 min following induction by 1 train of theta-burst stimulation (1TBS), indicating that this weak form of LTP is primarily postsynaptic. A presynaptic enhancement was found for LTP2 at 160 min after induction by 4TBSandfor LTP3 at 80 min and 160 min after induction by 8TBS. This demonstrates that more robust forms of LTP recruit a presynaptic component to their expressionandthat perhaps the onset of this recruitment may be earlier for more persistent LTP. Given that all three forms of LTP require unique postsynaptic signalling mechanisms for their induction and that LTP2 and LTP3 exhibit presynaptic changes, it is logical that there may be a retrograde signal (such as nitric oxide [NO]) released from postsynaptic spines. Disruption of NO signalling did not affect the persistence of LTP1, but blocked both LTP2 and LTP3 maintenance and the associated enhanced release.
This finding supports a role for NO signalling in the establishment of presynaptic changes associated with more persistent forms of LTP. The maintenance mechanisms associated with LTP1, 2 and 3 were next investigated by inhibiting translation and transcription. Data from these experiments established that LTP1 is independent of new gene transcription and protein synthesis. In contrast, LTP2 maintenance and its presynaptic expression were dependent on protein synthesis, but not gene transcription. LTP3 maintenance was dependent on both translation and transcription, but like LTP2 the enhanced release only required translation. Subsequent experiments using a membrane impermeable translation inhibitor indicated that new protein synthesis within the postsynaptic compartment is required for the enhanced presynaptic release.The present experiments provide a detailed examination of the expression and maintenance mechanisms underlying LTP1, 2 and 3. These results considerably strengthen the mechanistic separation of these forms of LTP, supporting a model of multiple discrete forms of LTP at CA3-CA1 synapses rather than different temporal phases. This is likely to explain some of the discrepancies in the LTP field and suggests that the pattern of afferent input to the hippocampus maydictate the mechanisms and duration of information encoding.
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