Award details

The Role of Multi-innervated Dendritic Spines in Memory Formation in Ageing

Reference	BB/J021687/1
Principal Investigator / Supervisor	Professor Mike Stewart
Co-Investigators / Co-Supervisors
Institution	Open University
Department	Science Interdisciplinary
Funding type	Research
Value (£)	271,109
Status	Completed
Type	Research Grant
Start date	01/02/2013
End date	31/01/2016
Duration	36 months

Abstract

Hippocampal ageing is associated with impairments in long-term potentiation (LTP). However, despite LTP deficits, aged rodents can form memory, raising the question as to which mechanism could be responsible? Our recently published study proposes a hypothesis for this. We have shown that in a knock-in mutant mouse lacking the autophosphorylation of alphaCaMKII that hippocampus-dependent memory can be formed despite fully blocked LTP and that this memory formation depends on the generation of multi-innervated dendritic spines (MIS), a particular type of synapse where a dendritic spine receives more than one presynaptic input. Further, we found that MIS-dependent memory is less flexible than memory relying on intact LTP. Here, we will test the hypothesis that in old age memory formation depends on MIS generation. We will train young adult and aged C57BL/6 mice in contextual fear conditioning and the Morris watermaze task. This will be followed by a quantitative 3D electron microscopic analysis of synapses and dendritic spines in hippocampal area CA1 and the dentate gyrus. Further, we will manipulate MIS generation by manipulating PSD-95, SAP97 and Kvbeta1.1 expression and to study the behavioural impact. PSD-95 and SAP97 overexpression will be used to increase MIS generation and PSD-95 as well as Kvbeta1.1 knock-down will reduce MIS generation. These molecular biological manipulations will be completed by pharmacological epxeriments that either enhance (NO donors) or reduce (rapamycin) MIS generation. Finally, we will study whether reconsolidation of hippocampus-dependent memory is impaired in old age as predicted by our hypothesis.

Summary

In old age the function of a brain region, the hippocampus, is compromised. This affects the making of new memories and we believe that it is also impairs the up-dating of newly acquired memories. With ageing the properties of nerve cells in the hippocampus change, impairing the communication between nerve cells. However, as the making of new memories is not fully abolished in old age, the question arises as to what mechanism accounts for memory making in old age. Our recent innovative collaborative study, published in PNAS, proposes such a mechanism. Using a mouse model, we have shown for the first time that the generation of a particular connection between nerve cells, so-called multi-innervated dendritic spines, leads to memory making when the strengthening of existing connections is impaired. This scaling effect of alterations of spines in distal neural circuits, in effect compensates for the synaptic impairments, which is confirmed by our recent data. The memory making that involves multi-innervated dendritic spines requires more training and it is less flexible in comparison to memory making relying on strengthening of existing connections. Our studies propose the hypothesis that in old age memory formation depends on the generation of multi-innervated dendritic spines and that because of this mechanism memory formation is slowed down and newly acquired memories are less flexible. Here, we will test this hypothesis. We will study hippocampus-dependent memory of young adult and aged mice after training in two behavioural tasks and we will investigate the impact of manipulations of the generation of multi-innervated dendritic spines.

Impact Summary

The main beneficiaries of the body of knowledge arising from this research are expected to be the academic community, in the first instance. We believe our anticipated findings will show that in old age hippocampus-dependent memory formation depends not only on modification of neural circuits in the hippocampus but specifically the generation of multi-innervated dendritic spines. These putative findings, based on our preliminary data published in PNAS, indicate that memory formation in old age, follows a pathway which compensates for inability to exercise synaptic plasticity as in younger animals where increases in synaptic number and neuronal density occur. The generation of MIS is, in effect, a scaling effect in neurons in old age. Secondly there is the opportunity for pharmacological manipulation of learning to stimulate in the hippocampus, up- and down-regulation of dendritic multi-innervated spines. This would potentially have importance for pharmaceutical companies concerned with developing cognitive enhancers, not only as a treatment for cognitive disorders in the normal population but especially disorders in ageing populations. Benefits will also be realised by staff working on this project who will have developed skills which are of very considerable importance in the medical and pharmaceutical fields, and thus be attractive to employers. The methodologies involved will employ genetically modified organisms, cutting edge microscopy techniques and cellular and molecular neuroscience methodology that put us and the research staff at the forefront of biomedical research. The beneficiaries will be engaged by presentations at meetings, publications of our results in peer-reviewed journals, reviews in more general journals such as Trends in Neuroscience, and information placed on our web sites in understandable language. Furthermore, we will communicate key findings though our public relation offices at the Open University and at King's College London.Both Prof. Stewart and Prof. Giese together with named investigators will present the research findings at meetings and write to ensure dissemination of research findings to the media. Profs Stewart and Giese both have extensive experience of talking to the media (the BBC and newspapers and magazines about their key research results), and also the lay public and are completely committed to the dissemination of science to the broadest possible audience.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Ageing, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/J021423/1 The Role of Multi-innervated Dendritic Spines in Memory Formation in Ageing

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