Role for glia-neuron interaction in the brain ageing and longevity

Maintaining brain function is very important for mental and physical health of individuals. The brain is composed of two major types of cells: neurons which transmit electrical signals and glial cells which maintain the wellbeing and function of neurons.
Recent discoveries highlighted the importance of interaction between neuronal and glial cells for many brain functions, like memory and cognition. Glial cells turned out to an active player in the brain. They can communicate with each other and neurons as well. They are capable to release neurotransmitters - small molecules transmitting chemical signals between cells. Glial cells also have receptors to these neurotransmitters - special proteins located in their membrane. One of the most important neurotransmitters that mediate bi-directional communication between neurons and glial cells are glutamate and adenosine-3-phosphate (ATP).

Through the course of life, glial cells maintain the wellbeing of neurons and protect brain tissue from neuronal over-excitability. Glia malfunction is related to many brain disorders such as ischemia, stroke, epilepsy, Alzheimer's disease and even effects of drug abuse. There is growing evidence, including our preliminary results, that the function of glial cells and their communication with neurons can change with age and these changes underlie frailty of the aged brain. Thus, glia-neuron communication may be of crucial importance for brain longevity and healthy ageing. However, age-related changes in astroglial signalling and their impact on brain longevity remain almost unexplored.

Research teams headed by the applicants have experience of whole-cell electrophysiological recordings and fluorescent imaging in brains of old animals. Our data on age-related alterations of glutamate- and ATP- mediated glial signalling have been recently published in the Ageing Cell - a leading international journal in the field. We have also developed a range of novel optogenetic and molecular tools for the study of astrocyte-to-neurone communication. The power of this approach is illustrated by our recent paper in Science which demonstrates another role for release of ATP from glial cells in the brain control of respiration. We wish to capitalise on this potential and propose a quantitative study of astrocytic control of age-related changes in communication between neurons and glial cells brain signaling.

The outcome of this research will be a new understanding of the role of astroglial cells in brain function and brain longevity. Results obtained will also contribute to further understanding of the physiology of ageing and will help to develop novel approaches for therapeutic interventions in neurological disorders and strategies for promotion of successful ageing

Brain function depends on the interaction between two cellular circuits, the electrically excitable neuronal network and glial cells which control cerebral circulation and homeostasis. Nowadays glial cells, especially brain astrocytes, are seen as competent participants of brain signaling. Astrocytes receive signals mediated by variety of neurotransmitters, integrate them and provide feedback to neighbouring cells by releasing gliotransmitter molecules. Important role for astrocytes in regulation of neuronal excitability, synaptic plasticity and neuro-vascular coupling has been demonstrated recently. It has also been shown that astrocytic dysfunction is implicated in the course of various age-related neurodegenerative diseases.

Our recent work highlighted the importance of glutamate and ATP-mediated signalling for neuron-glial communications. We have shown for the first time the age-related decline in the level of expression of glutamate and ATP receptors and Ca2+-signalling in the astrocytes of brain cortex. One can expect that age-related decline in astroglial control of synaptic transmission and neuro-vascular coupling may strongly affect many brain functions, in particular learning and memory. Thus, glia-neuron communication may be of crucial importance for brain longevity and healthy ageing. However, age-related changes in astroglial signalling and their impact on brain longevity remain almost unexplored.

The overall aim of the proposed project is to characterize the integrative role for astrocytes in aging brain. In particular, we shall test the hypothesis that age-related changes in glial modulation of neuronal signalling contribute to the decline in synaptic plasticity and memory. We shall also elucidate whether enriched environment and enhanced physical activity have a positive impact on glia-neuronal signalling and vascular-neuronal coupling in the aged brain.

Who will benefit from this research?

The proposed project is aimed at a better understanding of fundamental principles of brain ageing so we anticipate several stakeholder groups to benefit from our research. Beyond academic beneficiaries, these include: pharmaceutical industry, clinicians and the wider public, in particular local authority and health trusts, patients, care support groups and charities.


How will they benefit from this research?

Academic users will benefit from the large body of quantitative data on impact of ageing and enhanced activity on fundamental mechanisms of brain signalling, which will be disseminated through the normal routes of publications, reviews, presentations at meetings and data sharing. Scientists, especially postgraduate students and young postdoctoral researches, will also benefit from dissemination of our experience in the state-of-the-art experimental methods, through the workshops in electrophysiological recordings and ontogenetic techniques.

Although proposed research is not intended for immediate commercial exploitation, the pharmacological data obtained in the proposed experiments could provide an insight for the development of novel therapeutic agents specifically targeting the glial cells. Glial cells is a promising target for the development of new therapeutics and our research could benefit pharmaceutical and bioscience industry.

Our results will contribute to a better understanding of effects of ageing and enriched environment on synaptic transmission and plasticity. This may translate into local clinical trials of enrichment of cognitive and physical activity in hospital units, and facilitate potentially policy changes related to the findings. In longer term, this can help to enhance quality of life and creative output of aged population.
To facilitate this, we will communicate our results to the broadest professional audience possible. In particular, we will conduct seminars dedicated to the research into ageing and their medical and social implications, and engage sociologists, psychologists and health professionals to take part in this activity.

On a broader level, greater insight into interaction between two major classes of brain cells is of fundamental importance and will provide knowledge into brain development and the influence of age on the brain function. The general public, including schools, local charities and support groups, will benefit from opportunities to learn about this research on the web, in print and in person, which will increase the public knowledge base of the brain and nervous system. We will achieve this through the various forms of public communication and outreach activity, such as public lectures, university Open Days, web-conferences and publications in mass media.