Biomedical Engineering Reference
In-Depth Information
6.2. Astrocytic Ca
2
+
Signaling May
Increase Oxidative
Metabolism
Glutamate transporters (GluTs), which are mainly expressed in
the perisynaptic processes of astrocytes, play an important role
in removing the glutamate released during synaptic transmis-
sion preventing the extracellular glutamate concentration from
reaching excitotoxic concentrations
(56)
. Glutamate uptake is an
energy requiring process and stimulates the glycolytic metabolism
in cultured astrocytes
(57, 58)
. The main energy consuming pro-
cesses associated with glutamate transport into astrocytes include
extrusion of Na
+
and conversion of glutamate to glutamine
(59)
.
In the model proposed by Pellerin and Magistretti, astrocytes
utilize ATP produced from glycolytic glucose metabolism and
lactate is transported to neurons for oxidative metabolism
(57,
58)
. Because astrocytes express the full machinery for oxidative-
phosphorylation
(60)
, it is somewhat surprising that glutamate
uptake increases glycolysis rather than oxidative metabolism
(57)
.
A possible explanation is that the perisynaptic processes of astro-
cytes are essential devoid of most organelles (
Fig. 5.1
). The
fine processes of astrocyte covering synapses have a small diam-
eter (
m) and are almost devoid of mitochondria
(61)
.
Therefore, the glycolytic metabolism of glucose, most likely occur
in these fine structures of astrocytes which are heavily engaged
in glutamate uptake
(59, 62)
. Does oxidative metabolism in the
astrocytic cell bodies contribute to increased ATP production
during periods of intense glutamate uptake? Astrocytes contain
a large number of mitochondria and the mitochondria volume
fraction in the somatic areas of neurons and astrocytes are directly
comparable
(60, 61)
.
It is in this regard important to note that mGluRs are
expressed in the astrocyte perisynaptic processes in both rodent
and primate
(63, 64)
. Ex vivo experiments have shown that elec-
trical stimulation of Schaffer collaterals elicits mGluRs-dependent
Ca
2
+
elevation in hippocampal astrocytes
(5, 6)
. Depending on
the intensity of electrical stimulation, astrocytic Ca
2
+
signaling
can be detected either in the perisynaptic microdomains or
propagate intracellularly into the soma. Furthermore, activation
of astrocytic mGluRs contributes to increases of astrocytic Ca
2
+
signaling during sensory stimulation in vivo
(9)
. Astrocytic Ca
2
+
increases are first initiated in the perisynaptic processes and
propagate within a time frame of 0.5-2 s to the soma triggering
a 50-300% fold increase in cytosolic Ca
2
+
(9)
. Although little
is known about the role of Ca
2
+
signaling as a modulator of
glycolytic metabolism, it has been established that elevations
in mitochondria Ca
2
+
are strong stimulator of oxidative-
phosphorylation and accelerate ATP production
(65)
. Therefore,
we proposed that astrocytic Ca
2
+
signaling initiated in the perisy-
naptic processes following propagation into mitochondria rich
somatic regions may stimulate the oxidative-phosphorylation.
ATP produced by mitochondria in the soma may in turn diffuse
∼
0.3
μ
