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

Lead Research Organisation: King's College London
Department Name: Neuroscience


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.

Technical Summary

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.

Planned Impact

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.
Description We have discovered that memory is formed differently in young and old age. Mechanisms that are used in young age are not used in old age, and vice versa. This we have shown with molecular analyses and our partner Prof. Mike Stewart has illustrated it with ultrastructural studies. Our finding is a fundamental breakthrough as researchers thought that the same processes are used to make memory in young and old age, but that it would need just more training in old age to get the processes activated.

We have also found that memory in old age cannot be up-dated by retrieval as in young age. Taken together with our analysis of memory formation, we propose that memory storage differs with age and that the storage processes in old age do not allow for memory up-dating. More work is required for assuring that this novel hypothesis is correct.

Our project together with the work of our partner Prof. Mike Stewart has also identified a novel type of synaptic plasticity for memory formation, the generation of multi-innervated dendritic spines, a synapse type with two or more inputs. We suggest that this type of synaptic plasticity enables memory in old age. Recently, we found that pharmacological block of memory formation in aged mice, also prevents generation of multi-innervated dendritic spines, strengthening the hypothesis that these multi-input synapses are required for memory in old age.
Exploitation Route Our findings might be useful for companies trying to develop drugs to prevent age-associated memory impairment and memory impairment in diseases such as Alzheimer's disease. Specifically, such drug development should consider the impact on the generation of multi-innervated dendritic spines and memory up-dating in old age.

Our findings might also be useful for psychiatrists working with patients having post-traumatic stress disorder (a condition where a traumatic memory is persistently replayed without any up-dating). Our findings suggest that elderly might be more prone to develop post-traumatic stress disorder.

Finally, our findings might also be useful for the self-awareness of the general public. Specifically, there should be more tolerance, acceptance and help for the elderly when it is understood that elderly use a different brain mechanism to acquire information and that such mechanism impacts on modifiably of the memory.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

Title Adeno-associated viruses expressing PSD-95 versions 
Description We have generation adeno-associated viruses to overexpress either wild-type PSD-95 or PSD-95 without the PDZ2 domain, and additionalyl control viruses. These viruses will be used to manipulate the generation of multi-innervated dendritic spines in vivo. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact These recombinant viruses are useful tools to study the functional impact of generation of multi-innverated dendritic spines for memory formation and stability. 
Description EM analysis 
Organisation Open University
Department Department of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution EM analysis to assess generation of multi-innervated dendritic spines as memory mechanism in old age; this analysis also includes assessment of changes in other synapse types. For example, we found that memory formation in old age is not associated with formation of mushroom spines in contrast to young age. This suggests that an LTP-like plasticity is not induced in old age.
Collaborator Contribution Analysed synapse morphology after training in memory tasks in young and old age; currently, we are studying the impact of pharmacological treatment that impairs memory formation in old, but not young age.
Impact multi-disciplinary collaboration; we organized two international symposia (at BNA and a local FENS meeting) and had high-impact publications: Radwanska K, Medvedev N, Pereira GS, Engmann O, Thiede N, Moraes MFD, Villers A, Irvine EE, Maunganidze N, Pyza E, Ris L, Szymanska M, Lipinski M, Kaczmarek L, Stewart MG, Giese KP (2011). Mechanism of long-term memory formation when synaptic strengthening is impaired. Proc. Natl. Acad. Sci. USA 108, 18471-18475. Giese KP, Aziz W, Kraev I, Stewart MG (2015) Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation. Neurobiol. Learn. Mem. 124, 48-51.
Start Year 2010
Description Alzheimer's disease Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presented our research in form of a talk and a poster to the generla public in order to inform our insights how memory formation changes in old age and how synapses might deteriorate in dementia including Alzheimer's disease.
Year(s) Of Engagement Activity 2015
Description Collaboration with actor Toby Jones 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Worked on a you tube reflection with the actor Toby Jones on the cognitive process of waiting
Year(s) Of Engagement Activity 2013
Description Interview with David Edmonds, BBC on Forgetting 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Was interviewed by David Edmonds on 'forgeting'. This interview together with other interview was broadcasted by BBC radio.
Year(s) Of Engagement Activity 2015