Neuron-astrocyte coupling and its possible role in epilepsy

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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 suppor
                                          (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.

                                          – S Ramon y Cajal not electrically
                                          — astrocytes are
                                            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
                                                        Ca2 +
                         2QuickTime™2 +a
                    CaVideo dCa and
                           +
                                 ecompressor

                        Ca   2 + Ca2 +
                    are neede d to see this picture.
                                                           Ca2 +
                        Ca2 + Ca2 +                      uptake
         Ca2 +
                        Ca2 +
                                                           leak

Endoplasmic                         Ca2 +
Reticulum
      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.


                            Ulas et al., Glia 30, 352 (2000),
mGluR                        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 connecti
                                          tissue and muscle or gland cells, that is,
                                          passive weft for merely filling and suppo
                                          (and in the best case, a gangue for takin
                                           nutritive juices), constitutes the main
                                           obstacle that the researcher needs to
                                          remove to get a rational concept about
                                          the activity of the astrocytes and
                                         Arrangements ofneuroglia.
                                         neurons inyrat cortex
                                           —S Ramon 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

				
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