Properties and function of astroglial NMDA receptors: implications for plasticity of neuron-glial communication in the neocortex

Brain function is mediated by two classes of cell, the electrically excitable neurons and electrically non-excitable glial cells. For more than a century, glial cells were thought to play the role of structural and nutritional support neurons. Even their name means 'glue' (in Greek). Glial cells outnumber neurons 10:1 and this gives rise to the popular cliché that 'we use the potential of our brain only for 10 %'. The view on the function of glial cells / astrocytes and oligodendrocytes has undergone revolutionary change in recent years. Today glial cells are recognized as competent participants of brain communications and the interest of neuroscience laboratories in astrocyte and oligodendrocyte studies is rapidly growing. Glial cells have also become new targets for developing therapeutic agents for treatment of neurodegenerative disorders. My project will study signals generated in cortical astrocytes by glutamate - a very important transmitter of neuronal communications. Data obtained in the last decade have demonstrated the capability of glial cells to generate and receive signals mediated by 'classical' neurotransmitters such as glutamate. The actions of glutamate as a transmitter are mediated by several types of receptors. Of these, one of the most important is the NMDA receptor. These are critical for many brain functions, like memory and cognition and many brain pathologies such as ischemia and various neurodegenerative disorders. Until recently, NMDA receptors were thought not to be very important for the function of glial cells. The few groups who have undertaken work in this area have provided new insights. They have shown that glial NMDA receptors have properties different from neuronal ones and contribute to signaling between neurons and glial cells. Glial NMDA receptors may also be promising targets for the development of novel therapeutic agents for neurological disorders. However, this is hampered by incomplete current knowledge about the properties and functions of astroglial NMDA receptors. My project will provide the first detailed investigation of properties of NMDA receptors in the cortical astrocytes and their role in the astrocyte signalling. The outcome of my research will be new understanding of the pharmacological and functional properties of glial NMDA receptors.

Astroglial NMDA receptors have only been discovered very recently. These receptors, present in the spinal cord and neocortex, are potentially important for neuron-glial communication. The project will test the general hypothesis that glial NMDA receptors are involved in activity-dependent regulation of reciprocal signalling between neurons and astrocytes. This will be achieved through a combination of physiological (electrophysiology and fluorescent imaging) and molecular biological (single-cell RT-PCR) techniques. Experiments will be performed in cortical astrocytes in situ and acutely isolated astrocytes using transgenic mice expressing green fluorescent protein (GFP) under the control of the glial fibrillary acidic protein (GFAP) promoter. I propose to: (i) characterize expression and pharmacological and functional properties of NMDA receptors in neocortical astrocytes; (ii) characterize electrical and Ca2+ signalling triggered in astrocytes by activation of NMDA receptors; (iii) investigate the role of NMDA receptors in activity-dependent plasticity of astrocyte signalling. My research will provide a quantitative description of pharmacological and functional characteristics of NMDA receptors in cortical astrocytes which is necessary for understanding the fundamental roles of astrocyte in brain function.