When a mouse sees an object for just a few minutes, specific proteins inside its brain cells must be rapidly turned off to form a lasting memory of where that object was. This project tackles a fundamental gap in neuroscience: we know that forming memories requires both ramping up and silencing the production of synaptic proteins, but the molecular machinery that performs the silencing—and does so quickly enough to encode a memory from a brief glance—remains unknown. The researchers will identify which messenger RNA molecules are targeted for silencing by the proteins Argonaute and DDX6 in mouse hippocampal neurons immediately after a plasticity stimulus, and test whether blocking that silencing prevents the animal from remembering an object’s location. This is fundamental science. It will not produce a drug or a diagnostic test. But memory deficits are a core feature of dementia and normal ageing, and no effective treatments exist. Understanding the basic rules of how neurons coordinate rapid gene silencing could, in the long term, reveal entirely new molecular targets for therapies aimed at preserving or restoring memory. Past discoveries in fundamental neuroscience—such as the molecular basis of long-term potentiation—have similarly opened paths to cognitive enhancers and treatments for intellectual disability.
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Understanding how memories are formed is one of the foremost challenges in neuroscience. Recognition memory- the ability to remember things you've seen before- is essential for normal everyday living and is disrupted in neurological conditions, such as mild cognitive impairment and dementia. Hence increasing our knowledge of the molecular mechanisms underpinning memory is essential for the identification of novel targets for therapeutic intervention. In this project, we aim to fill gaps in our knowledge about how such memories are formed, and therefore provide essential clues about how this process goes wrong. To fulfil the brain's function of storing memories, neurons undergo extensive plasticity, i.e., they rapidly change their structure and function in response to incoming signals. There are several different types of memory, mediated by distinct forms of plasticity in different regions of the brain. For example, memory of an object's identity requires plasticity in a region called the perirhinal cortex, whereas memory of an object's location requires plasticity in the hippocampus. These types of recognition memory can be formed by seeing the objects for just a few minutes, and require dynamic changes in the synthesis of specific proteins - some increase, others decrease - that are involved in the structure and function of synapses. The molecular mechanisms that fine-tune these changes in synaptic protein synthesis are unclear. Protein synthesis can be controlled by "silencing" of messenger RNA (mRNA) molecules that encode the proteins. Silencing involves a different type of RNA called microRNA and specialised proteins called Argonaute and DDX6, which together bind to specific mRNAs to reduce protein synthesis. How this process happens at synapses quickly and coherently to mediate a particular type of recognition memory is unknown. By asking innovative questions with newly-developed model systems, we aim to define how the synthesis of groups of important synaptic proteins is regulated rapidly and in a coordinated manner to mediate plasticity in the hippocampus and hence drive the formation of object location memories. This aim is underpinned by the following hypotheses, which we will address in this proposal: 1) In response to a plasticity stimulus in mouse hippocampal neurons, Argonaute binds rapidly to a specific group of mRNAs that encode proteins involved in synaptic structure and function. 2) DDX6 confers specificity in the mRNA selection process and consequent silencing. 3) Silencing of the selected mRNAs is necessary for hippocampal plasticity and consequently, for memory of an object's location. Our objectives are to test these hypotheses by isolating and identifying mRNAs that increase their binding to Argonaute and DDX6 within a few minutes after a plasticity stimulus. We will carry out in-depth analysis of the mRNA sequences to define the specific sites on the mRNA where Argonaute and DDX6 bind, and consequently probe the mechanism involved. Ultimately, we will investigate whether preventing the silencing of individual novel genes in mice affects plasticity and memory. This project aligns with BBSRC's 'Understanding the Rules of Life' priority area. By identifying previously-undiscovered gene regulatory mechanisms that are essential for rapid neuronal plasticity, our work will increase our understanding of how we form new memories. Since deficits in memory are symptomatic of numerous neurological disorders and normal ageing, which pose significant challenges to the UK's economy and society, it is essential to understand the mechanisms of memory formation and uncover potential therapeutic targets.
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