The role of neuronal activity in Wnt-Fz mediated synapse formation
Lead Research Organisation:
University College London
Department Name: Cell and Developmental Biology
Abstract
The formation of functional neuronal circuits in the brain requires coordinated communication between nerve cells (called neurons). Cells communicate or signal to each other by releasing molecules that act on neighbouring cells. Importantly, recipient cells can detect these released signals because they have structures located at the cell surface, called receptors, that act as antennas for these signals. Once recipient cells detect the signals through their receptors, a series of events inside the cell, called signalling cascades, are activated. These cascades can have profound effects on cellular function. For instance, they can lead to the assembly of specialised connections between neurons, called synapses, which are crucial for brain functions such as learning and memory.
In addition to secreted molecules, the firing pattern of neurons, called neuronal activity, can also influence the communication between neurons by regulating the local production and/or the release of secreted signals as well as the localisation of their receptors at the cell surface. However, how neuronal activity regulates these secreted signals, and their receptors remains poorly understood.
Previous work from our lab has led to the discovery that specific factors released by neurons, called Wnt proteins, play a critical role in the formation of brain circuits. We found that Wnt7a, a member of this family of proteins, promotes the formation and function of synapses in different brain areas. We have focused our attention on the role of Wnt7a in the hippocampus, a brain area required for learning and memory. Wnt proteins elicit different responses in cells through their interaction with surface receptors. For instance, we have identified Frizzled-5 (Fz5), a key receptor for Wnt7a in neurons. The binding of Wnt7a to the Fz5 receptor at the cell surface of neurons promotes synapse formation. Notably, we recently discovered a novel mechanism that modulates the level of the Fz5 receptor at the cell surface and its ability to promote the formation of synapses. This mechanism is through the additon of lipid moieties to the receptor. Interestingly, this process is modulated by neuronal activity.
In this project, we will examine the precise molecular mechanisms by which Wnt7a levles and Fz5 localisation are regulated by neuronal activity. We will focus specifically on a pattern of neuronal activity termed long-term potentiation (LTP). As its name implies, LTP leads to the persistent strengthening of synapses and is considered the main mechanism that underlies learning and memory. We will use a multidisciplinary approach that uses biochemical and state-of-the-art live-cell imaging techniques combined with modulation of gene function and activation of specific neuronal connections using light (using a technique called optogenetics) in hippocampal neurons. This project will provide novel mechanistic insights into how signalling molecules and neuronal activity contribute to the formation of complex neuronal connections.
In addition to secreted molecules, the firing pattern of neurons, called neuronal activity, can also influence the communication between neurons by regulating the local production and/or the release of secreted signals as well as the localisation of their receptors at the cell surface. However, how neuronal activity regulates these secreted signals, and their receptors remains poorly understood.
Previous work from our lab has led to the discovery that specific factors released by neurons, called Wnt proteins, play a critical role in the formation of brain circuits. We found that Wnt7a, a member of this family of proteins, promotes the formation and function of synapses in different brain areas. We have focused our attention on the role of Wnt7a in the hippocampus, a brain area required for learning and memory. Wnt proteins elicit different responses in cells through their interaction with surface receptors. For instance, we have identified Frizzled-5 (Fz5), a key receptor for Wnt7a in neurons. The binding of Wnt7a to the Fz5 receptor at the cell surface of neurons promotes synapse formation. Notably, we recently discovered a novel mechanism that modulates the level of the Fz5 receptor at the cell surface and its ability to promote the formation of synapses. This mechanism is through the additon of lipid moieties to the receptor. Interestingly, this process is modulated by neuronal activity.
In this project, we will examine the precise molecular mechanisms by which Wnt7a levles and Fz5 localisation are regulated by neuronal activity. We will focus specifically on a pattern of neuronal activity termed long-term potentiation (LTP). As its name implies, LTP leads to the persistent strengthening of synapses and is considered the main mechanism that underlies learning and memory. We will use a multidisciplinary approach that uses biochemical and state-of-the-art live-cell imaging techniques combined with modulation of gene function and activation of specific neuronal connections using light (using a technique called optogenetics) in hippocampal neurons. This project will provide novel mechanistic insights into how signalling molecules and neuronal activity contribute to the formation of complex neuronal connections.
Technical Summary
Synapse assembly is a crucial step in neuronal circuit formation in the brain. Numerous signalling molecules and their receptors have been identified as key modulator of synapse assembly. Neuronal activity also plays a role in synapse formation and function. For example, neuronal stimulation by rearing animals in an enriched environment results in profound changes in synapse formation and growth through the modulation of secreted molecules. However, we have a limited understanding of how neuronal activity influences signalling pathways that regulate neuronal circuit formation.
Our lab has been studying the role of Wnt signalling in the formation of neuronal connections in the vertebrate nervous system. We found that Wnt7a promotes synapse formation and function in the hippocampus. This Wnt protein requires the Frizzled-5 (Fz5) receptor to regulate synapse formation. Importantly, long-term potentiation (LTP), a paradigm that induces persistent synaptic strength and underlies learning and memory, increases endogenous levels of Wnt7a at dendritic spines and the presence of Fz5 at the plasma membrane, further enhancing Wnt signalling. However, the mechanisms by which LTP induction triggers these changes are currently unknown.
In this project, we will interrogate the interplay between LTP induction and Wnt7a/Fz5 levels during the formation of synapses in the mammalian brain. We will use a multidisciplinary approach that combines molecular and biochemical analyses, time-lapse imaging of fluorescently labelled molecules and modulation of neuronal connectivity using optogenetic approaches. Our studies will provide a detailed understanding of the molecular mechanisms that contribute to activity-mediated synaptic connectivity in the mammalian brain. Given that Wnt signalling enhances synaptic connectivity by promoting neurotransmitter release and synaptic strength, our studies will shed new light onto positive feedback mechanisms controlling neuronal connectivity.
Our lab has been studying the role of Wnt signalling in the formation of neuronal connections in the vertebrate nervous system. We found that Wnt7a promotes synapse formation and function in the hippocampus. This Wnt protein requires the Frizzled-5 (Fz5) receptor to regulate synapse formation. Importantly, long-term potentiation (LTP), a paradigm that induces persistent synaptic strength and underlies learning and memory, increases endogenous levels of Wnt7a at dendritic spines and the presence of Fz5 at the plasma membrane, further enhancing Wnt signalling. However, the mechanisms by which LTP induction triggers these changes are currently unknown.
In this project, we will interrogate the interplay between LTP induction and Wnt7a/Fz5 levels during the formation of synapses in the mammalian brain. We will use a multidisciplinary approach that combines molecular and biochemical analyses, time-lapse imaging of fluorescently labelled molecules and modulation of neuronal connectivity using optogenetic approaches. Our studies will provide a detailed understanding of the molecular mechanisms that contribute to activity-mediated synaptic connectivity in the mammalian brain. Given that Wnt signalling enhances synaptic connectivity by promoting neurotransmitter release and synaptic strength, our studies will shed new light onto positive feedback mechanisms controlling neuronal connectivity.
