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Understanding contribution of glial cells in memory encoding, storage and retrieval and factors that influence it
Secondary Supervisor(s): Professor Jose Gutierrez-Marcos
University of Registration: University of Warwick
BBSRC Research Themes: Understanding the Rules of Life (Neuroscience and Behaviour)
Project Outline
Why is this important?
Memory is an essence of life. It allows us to remember things to influence our future decisions. Memory formation is a very dynamic process. Neuronal synaptic plasticity such as long-term potentiation (LTP), long-term depression (LTD) and synaptic scaling that weakens and strengthens selective synapses is the foundation of memory formation and consolidation. These plasticity events play an important role in the process of memory encoding, storage and retrieval. Despite of decades of research in this field, basis of memory and processes that influence it are nor completely understood.
Background
Neuronal synaptic plasticity makes the basis of memory. However, this process can be influenced by non-neuronal brain cells called glia. Glial cells control synaptic communication and plasticity. For example, astrocytes regulate neurotransmitter uptake and modulates the concentration of transmitter available at synapses, whereas microglia can secrete neurotropic and supportive factors or pro- and anti-inflammatory molecules to influence neuronal homeostasis. Notably, microglia1 and astrocytes2 can influence memory formation and retrieval, but we still do not completely know the mechanism behind it.
Objectives
Neuronal action potentials or Ca2+ currents (that underlies theta oscillations implicated in learning and memory) and can be studied using genetically encoded calcium indicators and the state-of-the-art in vivo deep brain imaging and in vitro technique. We have found in our lab that hyperactivity of neurons in certain neurological conditions such as epilepsy characterised by seizures (an excessive uncontrolled electrical activity in the brain) increases expression of certain protein on astrocytes or microglia that can alter the LTP and LTD processes.
Figure 1. Hemichannel expression in CA1 astrocytes in healthy and brain with hyperactive neurons.
Orange arrow represents the increased astrocytic hemichannel expression. Scale bar- 20µm.
Figure 2. Hemichannel blockage has no effect on memory process (LTP) in healthy brain compared to brain with hyperactive neurons.
Specific objectives
1. Understanding how hyperactivity of neurons alters the glial cells profile.
2. Investigating whether altered glial cells’ profile influences memory processes in in vitro and/or in vivo models.
3. Can altering glial cells protein expression profile enhance memory function.
Method
We will utilise both in vivo (memory testing/imaging in rodents) and in vitro (electrophysiology, immunohistochemistry, western blot) approaches to accomplish this project. Different genetic and/or pharmacological methods will be used to achieve these objectives. Throughout this project, currently available sequencing data will be reviewed and analysed, such as RNAseq, ATACseq to identify important molecular targets that can be experimentally tested and studied. Prof Gutierrez-Marcos is an expert in transcriptomic field and project will significantly benefit from his expertise.
Project Outcome
Project will transform our understanding of how changes in activity of glial cells due to hyperactivity of neurons alters the memory process along with key molecular targets involved in this process. This will further allow us to identify and target these molecules in certain conditions where expression of these molecules’ changes.
References
1. Wang, C. et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science 367, 688-694 (2020).
2. Orr, A. G. et al. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat. Neurosci. 18, 423-439 (2015).
