Bioenergetic role of astrocytes in neuronal plasticity and behaviour

点击翻译按钮获取中文摘要

Astrocytes play active roles in synaptic function, regulating neurotransmission in various means including metabolic support of neuronal activity. Astrocytes are the only brain cell capable of energy storage, which is stocked as glycogen inside these cells. This energy reservoir can be rapidly mobilised in response to changes in neuronal activity and has been shown to influence synaptic plasticity on the cellular level, regulating learning, memory, and decision making in vivo. Despite abundant evidence describing a critical role of the astrocyte to neuron L-lactate shuttle, there is also experimental evidence undermining this work. Indeed, it has also been demonstrated that neurons can rely on their own glycolysis for energy production and do not require `pre-processing' of glucose into L-lactate by astrocytes. These opposing observations have led to heated debate in this field, which remains unresolved. In this proposal we aim to experimentally dissect the influence of astrocyte L-lactate in distinct aspects of synaptic transmission, plasticity, and behaviour. We will carry out a detailed investigation combining distinct molecular, functional, and imaging approaches, which is severely lacking in this domain. My research program will be divided into three distinct aims; 1.We will investigate the dependence of distinct forms of synaptic transmission and plasticity on the astrocyte to neuron L-lactate shuttle. This will be achieved using patch clamp electrophysiology and pharmacology targeting both neurons and astrocytes to determine specifically whether distinct forms of short and long-term plasticity require L-lactate from astrocytes. 2.We will determine the spatiotemporal dynamics of the astrocyte to neuron L-lactate shuttle using two-photon imaging of genetically encoded fluorescent sensors for L-lactate. These sensors will be virally targeted to neurons or astrocytes using cell-specific promoters, and changes in extracellular L-lactate in response to synaptic stimulation will be quantified. 3.We will examine the role of astrocyte to neuron lactate shuttle in distinct behaviours comparing learned versus innate behaviours. These are distinct in that learned behaviours require repeated exposure and training, known to evoke long-term synaptic plasticity and memory formation, whereas innate behaviours, such as response to predator, do not require training or learning. Perspectives: This work will allow us to unravel the complexities of the astrocyte-neuron L-lactate shuttle, defining L-lactate-dependent and -independent synaptic and behavioural processes. Our detailed investigation will represent a significant advancement in the field of astrocyte-neuron metabolic coupling, shedding further light on the complexity of this biological process and resolving a long-standing debate in this field.