Download Neural activity

The Possible Roll of a NeuronAstrocyte Signaling Pathway in
Regulating Vascular Tone
Presented by Chris Sherman
Presentation Structure
1) Critical look at Neuron to Astrocyte Signaling Pathways
-Research conducted by Cornell-Bell et al.
-Calcium Wave Propagation
2) Critical look at Astrocyte to Neuron Signaling Pathways
-Astrocytic Glutamate release
-Research conducted by Parpura et al.
3) Neuron-Astrocyte-Endothelial Cell Signaling Pathways
-Research conducted by Zonta et al
-Regulation of Gap Junctional Expression
-Neural activity-dependent vasodilation
4) Implications of a ‘Three-Part Synapse’
5) Future Research
Neuron to Astrocyte Signaling
IV. Intracellular levels
of Ca++ rise.
Cytoplasmic InsP
activates the first of
the Ca++ vesicles,
but once levels of the
later rise, free Ca++
releases other pools
of vesicular-bound
Ca++.
II. Metabotropic receptors for
Glutamate (mGluR) located on
astrocyte bind synaptic Glutamate.
Subsequent intracellular
Phospholipase C release leads to
Inositol Triphosphate (InsP3)
production.
I. Glutamate release from pre-synaptic
neuron
As activity increases at the
synapse, more astroccytic
mGluR are activated. This
ultimately leads to an
increased level of vesicularbound Ca++ release into the
cytoplasm of the astrocyte.
When Cornell-Bell et al
published this finding over a
decade ago, it forced science
to take a more critical look
at the role astrocytes play in
the brain.
III. Vesicular ionotropic
InsP3-mediated receptors
bind InsP3. Ion channels
open, allowing vesicularbound pools of Ca++ into
the intracellular
enviornment.
Glutamate Induces Calcium Waves in Cultured Astrocytes: A Form of
Long-Range Glial Signalling
Cornell-Bell et al
Major Findings
Low and High Neural Activity encoded by Astrocytes in the Frequency of Ca++ Oscillations
Neural Activity
Period between Calcium Peaks
Existance of two GluR subtypes on Astrocytic membrane: Kainate and Quisqualate
Kainate Receptors:
(ionotropic)
Quisqualate Receptors:
(metabotropic)
Synaptic cleft
[Ca++]
Astrocytic Intracellular
[Ca++]
Probability of
Neurotransmitter
release in synapse*
2nd messenger
Phospholipase C
Inositol Triphosphate
in Cytoplasm
Vesicular release of Ca++
into Cytoplasm of
Astrocyte
*
(Katz and Miledi et al.)
Glutamate Induces Calcium Waves in Cultured Astrocytes: A Form of
Long-Range Glial Signalling
Cornell-Bell et al
It is unlikely that sufficient neurotransmitter at one astrocytically-enveloped synapse could provoke a calcium wave.
An individual Astrocyte, however, can envelop many synapses in vivo. Exposure to neurotransmitters at multiple
synapses is most likely the necessary factor in calcium wave production.
Astrocyte to Neuron Signaling Pathways
Excitatory Action on Pre-Synaptic Neuron: NMDA Ionotropic Receptors bind
Glutamate; ion channel opens and influx of Ca++ follows (Parpura et al. 1994).
Excitatory action stems from subsequent exocytosis of neurotransmitter-containing
vesicles; this occurs due to the increase in intracellular [Ca++]. Specific action of
Ca++ on vesicles is not known.
Excitatory Action on PostSynaptic Neuron: NMDA Ionotropic
Receptors bind Glutamate; ion channel
opens and influx of Ca++ follows. This
causes a membrane-wide
depolarization.
Inhibitory Action on Presynaptic Neuron: Kainate GluR’s
have been shown to modulate
inhibitory transmissions, possibly
through the release of GABA
(Qing-song Liu et al., 2003).
I. Ca++ wave from synctyium
reaches distal Astrocyte; ions cause
glutamate-containing vesicles to
release their payload into the
synaptic cleft via exocytosis. In
addition to signaling to these
vesicles, the Ca++ ions also move
into the synaptic cleft themselves
(Nedergaard et al., 1994). 30 years
ago demonstrated that free Ca++
presence in the synaptic cleft
increases the probability of presynaptic neurotransmitter
release (Katz and Miledi, 1967).
Glutamate-dependent Astrocyte Modulation of Synaptic Transmission Between
Cultured Hippocampal Neurons
Parpura et al., 1994
To confirm that the increase in neuronal Ca++
was due to an astrocytic-dependant pathway (in
contrast to synaptic), Parpura introduced a
mGluR antagonist, d-glutamylglycine, into the
cell co-culture. As expected, neuronal [Ca++]
remained constant.
Parpura measured neuronal [Ca++] after Bradykinin
injection, and found that Ca++ waves in astrocytes induced
a neural Ca++ rise. This leads to a greater potential for
synaptic activity.
When [Ca++] rises in astrocytes adjacent to the
co-cultured neurons, glutamate is released
(through exocytosis) and binds to ionotropic
glutamate receptors on the neural membrane.
This opens Ca++ ion channels to, and
extrasynaptic Ca++ flows into the neuron.
Parpura et al. introduced Bradykinin, an exogenous
neuro-ligand, into the neuron-astrocyte co-culture.
This glutamate receptor agonist bound to
metabotropic glutamate receptor sites on a distal
Astrocyte. Intracellular [Ca++] rises, eventually
propagating into a global wave.
Cerebral Circulation
As Neural activity
there is an
Energy requirement
To solve this…
Astrocytic uptake of Glutamate leads to> ADP leads to>
Glycolysis within Astrocytic
endfeet which finally leads to> Lactate delivered to neuron
=Energy demand met! But what about OXYGEN? Waste? Other nutrients?
With increased neural activity, there MUST be an increase in LOCAL CIRCULATION OF
BLOODFLOW
Neuron-to-astrocyte signaling is central to the dynamic
control of brain microcirculation
Zonta et al., 2003
Neural Activity
Ca++ propagation throughout
astrocytic syncytium
[Ca++] at endfeet attached
to endothelial cells
Vesicular release of prostanoids
Relaxation of capillary walls;
decrease in vascular tone
Bloodflow
Synchronous Firing Groups- Astrocytic Regulation of Neural Networks
Gap Junctions
Capillary-Tropic
Neuronal Upregulation
Neuronal or Astrocytic
control?
Future Research
-fMRI studies
-Pathology
-Specific action of Ca++ on Astrocytic vesicles (this is not specific to Astrocytes;
research on the general mechanisms behind neuronal vesicular release of
neurotransmitters is lacking as well)
-Inhibitory action of Kainate receptors (both neuronal and astrocytic)
-In vivo research
-Cognitive functioning
-Pharmacology
-Overall models of how neurons integrate information
References
1) Katz B, Miledi R. The timing of calcium action during neuromuscular transmission. J
Physiol (Lond) 1967;189: 535-544.
2) Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. Glutamate induces calcium waves in
cultured astrocytes: long-range glial signaling. Science 1990;247:470-473.
3) Katz B, Miledi R. The timing of calcium action during neuromuscular transmission. J
Physiol (Lond) 1967;189: 535-544.
4) Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate-mediated
astrocyte-neuron signaling. Nature 1994;369:744-747.
5) Qing-song Liu, Qiwu Xu, Gregory Arcuino, Jian Kang, and Maiken Nedergaard. Astrocytemediated activation of neuronal kainate receptors. PNAS. 2004; 101: 3172-3177
6) Nedergaard M. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells.
Science 1994; 263:1768-1771.
7) Micaela Zonta, María Cecilia Angulo, Sara Gobbo, Bernhard Rosengarten, A. Hossmann, Tullio Pozzan
and Giorgio Carmignoto. Neuron-to-astrocyte signaling is central to the dynamic control of brain
microcirculation. Nat. Neurosci. 6, 43–50 (2003).