Transcript Neuron-astrocyte coupling and its possible role in epilepsy

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