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Neuron-Astrocyte Coupling and its possible role in Epilepsy P. Jung, Department of Physics and Astronomy, Ohio University The prejudice that the relation between neuroglial fibers and neuronal cells is similar to the relation between connective tissue and muscle or gland cells, that is, a passive weft for merely filling and support (and in the best case, a gangue for taking nutritive juices), constitutes the main obstacle that the researcher needs to remove to get a rational concept about the activity of the neuroglia. – astrocytes are not electrically —S Ramon y Cajal excitable but Ca2+ excitable - one astrocyte contacts 1000s of synapses Nedergaard et al., TINS 26, 523 (2003) Ramon y Cajal Astrocytes are Ca2+- excitable ATP, Glutamate IP3 2+ Ca 2 + QuickTime™ and a Ca Video decompressor are needed to see this picture. 2 + Ca2 + Ca2 + Ca Ca2 + Ca2 + Ca2 + Ca2 + Ca2 + uptake leak Endoplasmic Reticulum Ca2 + Cultured rat hippocampal astrocytes A.H. Cornell-Bell at al. Science, 247, 373 (1990) Intercellular Ca2+ Waves (Cornell-Bell et al., M. Sanderson, A. Charles) Speed: ~20µm/s Range: a few hundred µm Time scale: seconds to minutes Neurons talk to Astrcoytes Astrocyte processes enwrap synapse mGluR Tripartite Synapse Fellin ei al., Physiology 21, 208 (2006) (Araque et al. Trends Neurosci 22 (1999)) In-vivo: whisker stimulation Wang et al., Nat Neurosci 9 (2006) (Nedergaard lab) Whisker stimulation (mice) Field - potential recording (barrel cortex) Astrocyte Ca neurons (red arrow) Astrocytes talk back to Neurons through release of glutamate Micro-island: neuron on astrocytes (culture) Parpura & Haydon, PNAS, 97 (2000) In slice: Fellin et al. , Neuron 43 (2004) Synchronized SICs in small domains (Fellin et al., Neuron 43 (2004)) Glutamate released from astrocyte activates slow, synchronous NMDA-mediated inward currents in domains of neurons Astrocytes and Epileptic Seizures Tian et al.:An astrocytic basis of epilepsy (Nature Medicine, 11 (2005) Epileptic discharges through local paroxysmal depolarization shift (PDS) driving groups pf neurons into synchronous bursting activity. -- Ca2+ increased in Astrocyte – PDS - like epileptiform responses in neighboring neurons – PDS in nearby neurons in in-vitro epilepsy models with blocked synaptic transmission – Anti-epileptics reduced Ca2+ signal in astrocyte Epilepsy and astrocytes – in astrocytes from epileptic foci mGluRs are overexpressed by a factor of about 20 (rat models and human) (Ulas et al., Glia 30, 352 (2000), Tang and Lee, J. Neurocytology, 30, 137 (2001), Aronica et al. Europ.J. Neurosci., 12, 2333 (2000), – Enhanced IP3 Hydrolysis and increased Ca2+ spikes during epileptic seizure (Ong et al. J. Neurochem. 72, 1574 (1999) – More spontaneous astrocytic calcium spikes in epileptic (Tashiro et al., J. Neurobiol. 50, 45 (2002) Neuron-astrocyte feedback model (S.Nadkarni and P.J., Phys. Biol. 1 (2004)) Large abundance of mGluR Astrocytes from epileptic foci: mGluRs are increased by a factor of about 20. mGluR Ulas et al., Glia 30, 352 (2000), Tang and Lee, J. Neurocytology, 30, 137 (2001), Aronica et al., Europ.J. Neurosci., 12, 2333 (2000) Publications S. Nadkarni and P.J., Dressed Neuron:modeling neural-glial interactions,Phys. Biol. 1, 35 (2004) S. Nadkarni and P.J., Synaptic inhibition and pathological hyperexcitability through enhanced neuron-astrocyte interaction J.Integr. Neurosci, 4, 1 (2005) S.Nadkarni and P.J., Modeling synaptic transmission of the tripartite synapse, Phys. Biol. 4, 1 (2007) S. Nadkarni, P.J. and H. Levine, Astrocytes optimize synaptic transmission of information, submitted Astrocytes and Neurons The prejudice that the relation between neuroglial fibers and neuronal cells is similar to the relation between connective tissue and muscle or gland cells, that is, a passive weft for merely filling and support (and in the best case, a gangue for taking nutritive juices), constitutes the main obstacle that the researcher needs to remove to get a rational concept about the activity of the neuroglia. Arrangements of astrocytes and neurons in rat cortex —S Ramon y Cajal – astrocytes are not electrically excitable but Ca2+ excitable - one astrocyte contacts 1000s of synapses Nedergaard et al., TINS 26, 523 (2003) Ramon y Cajal
