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

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.

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.

Who will benefit from this research?

Life expectancy is continuously increasing in developed countries. However, the aged population has a relatively low quality of life, primarily due to age-related learning and memory impairments. Accordingly, there is a great interest in research that has direct or indirect potential to enhance learning and memory abilities in old age. Our research falls into this category. Thus, next to academic community, who will be the main beneficiaries, the following groups will benefit from our research:
1) Drug companies with an interest in developing memory enhancing pharmaceuticals for the elderly.
2) Heath care systems that are interested in minimizing the costs for the care of elderly.
3) Aged individuals seeking to improve their learning and memory abilities.
4) Benefits will also be realised by research 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.
5) The methodologies involved will be of importance in informing researchers in the ageing field, of the new methodology to be used; we will employ genetically modified organisms, cutting edge microscopy techniques and cellular and molecular neuroscience methodology



How will they benefit from this research?

Our research will provide mechanistic understanding of age-related learning and memory impairments. This mechanistic understanding will be instrumental in devising pharmacological approaches to enhance learning and memory abilities in old age (ideally, the enhancement is to the level of the individual at young age). Therefore, drug companies with an interest in developing cognitive enhancing drugs will benefit from our research. Additionally, aged individuals will benefit as our research will be a milestone toward improving their quality of life. Finally, the costs for care of the elderly are very high, in part because of the decline of cognitive abilities. In the current difficult economic climate it is the interest of various politicians (and possibly society as a whole) to minimize the costs for care by developing treatment.

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.