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March 2004: Discuss the evidence that the hippocampus has a role in the laying down of
memory and the mechanisms by which this may occur. Do clinical disorders of memory
help us understand these processes?
March 2005: What is known about the cellular mechanisms involved in learning and
memory?
June 2005: What is the pharmacological evidence supporting our understanding of how
long-term potentiation occurs?
September 2005: What do we know of the synaptic circuitry and functions of the
hippocampus?
March 2006: Discuss the mechanisms underlying Long Term Potentiation in the
hippocampus.
9. What happens in Long Term Potentiation (LTP)? What is the function of LTP in EITHER
brain development OR memory?
12 answers (mean mark 5.6) with excellent descriptions of LTP and its molecular basis.
Rather weaker on the role in memory and only one candidate tried to address the role in
development.
1. Discuss the evidence that the hippocampus has a role in the laying down of memory and the
mechanisms by which this may occur. Do clinical disorders of memory help us understand
these processes?
36 answers, mean mark 5.4. The answers to this question disappointed by not addressing the
question directly. Most students introduced the topic by referring to H.M., but did not
provide other specific evidence for the function of the hippocampus in memory. Most
students took for granted that long-term potentiation is the mechanism involved without
further discussion. Most students gave examples of clinical disorders but failed to describe
how they help us understand memory processes.
6. What is known about the cellular mechanisms involved in learning and memory?
49 answers; average mark 5.3
In addressing this question, most of the students wrote an essay on hippocampal
long-term potentiation. The best answers offered alternative mechanisms involved
in different brain structures and a critical discussion of the experimental evidence
linking synaptic plasticity with learning and memory.
The main type of LTP is mediated by NMDA receptors (NMDAR) and its
activation depends on both glutamate and postsynaptic depolarisation which explains the
characteristics of LTP: cooperativity, associativity, and input specificity. LTP can be
induced by tetanic stimulation of a presynaptic cell or by weak activation of many
presynaptic cells that converge to a single dendritic spine, a feature called cooperativity.
Furthermore, strong activation of one set of synapses can depolarize adjacent regions and
so facilitate LTP at an independent set of adjacent active synapses provided that
stimulation at synapses occur simultaneously. This associativity provides the cellular
mechanism for associative or classical conditioning. Finally, only the postsynaptic
membrane at the site of glutamate release exhibits LTP so that LTP is input specific. This
is because the critical trigger for inducing LTP, Ca2+ influx, is localised only to that
dendritic spine.
The influx of Ca2+ also induce the late phase of LTP which involves activation of
transcription factors resulting in strengthening of the postsynaptic response due to
increased protein synthesis and synaptic remodelling.
SLOBBO DIAGRAM SHOWING EXPRESSION OF LATE PHASE OF LTP. SEE FIG.
63-13 P.1265
In conclusion, our study of LTP has led us to understand how LTP is involved in
learning and memory. Disruption of LTP may lead to memory deficits and it has been
proposed that memory loss during the early stages of Alzheimer’s disease (AD) is due to
disruption of hippocampal LTP (see Chen et al. 200). Amyloid β (Aβ) peptides are
believed to contribute to the pathogenesis of AD. Experimental studies demonstrated that
brief perfusion of hippocampal slices with low concentrations of Aβ significantly
inhibited LTP induction without affecting the basal synaptic transmission in the Schaffer
collateral-CA1 pathway. Furthermore, Aβ variants that lack neurotoxic and aggregating
properties were able to block LTP suggesting that this effect is neurotoxicity
independent. The mechanism by which Aβ impairs LTP is unclear but may be due to
transient changes in intracellular Ca2+ concentrations by interacting with existing ion
channels or formation of de novo ion channels. For example, intracellular Ca2+ transients
may activate calcineurin which can desensitize NMDAR (Tong et al. 1995). It is hoped
that a better understanding of the mechanism by which Aβ inhibit LTP will lead to
development of pharmacological treatments that reduce memory loss in AD patients.