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Astrocytes are chemically excitable
astrocyte receptors for:
norepinephrine
glutamate
GABA
acetylcholine
histamine
dopamine
adenosine
ATP
1
gliotransmission:
gliotransmitters:
• glutamate
• ATP/adenosine
• D-serine
• nitric oxide
• PGs
• ANP, taurine
no evidence for GABA release
2
CICR
3
+
cADPR
+
CICR: Ca2+-induced Ca2+ release
4
CD38
ADPribosyl
cyclase
cADPR
hydrolase
Cyclic ADP-ribose (cADPR)
5
6
neuronal synchrony
7
ATP
8
9
Ca2+
ectonucletidases
5′-nucleotidase
heterosynaptic depression
cAMP
hyperpol.
10
11
12
100 Hz for 1 s
S1
long-term potentiation
S2
heterosynaptic depression
unstimulated
13
Adenosine is an endogenous sleep factor:
its level is increased during awakening and lowered during sleep
Sleep deprivation  memory loss and attention deficits,  risk of AD
14
Caffeine blocks the effects of adenosine
15
Ca2+
NMDAR
ASCT = amino acid transporters
VRACs = Volume-regulated anion channels
Phgdh = 3-phosphoglycerate dehydrogenase
SR = serine racemase
Degradation of D-serine blocks LTP induction
16
a rise in astrocyte intracellular Ca2+ controls LTP at nearby synapses via D-serine
no D-Serine
HFS = high-frequency stimulation
17
Osmoreception in magnocellular neurosecretory cells (MNCs)
primary osmoreceptors
increased
osmolarity
decreased
osmolarity
VRA = volume regulated anion channel
SIC = stretch-inactivated cation channel
GlyR = glycine receptor
increased
osmolarity
18
Depression = fewer astrocytes
Epilepsy, Parkinson's disease, Alzheimer’s disease = astrocytes more reactive
Adenosine is a powerful anticonvulsant, but its use is limited by the different
effects of adenosine on the brain depending on the receptors
19
Astrocytes provide antioxidant power to neurons
GSH, being hydrophilic, cannot passively diffuse through the
lipid border of the BBB.
The typical concentration of GSH in neurons is around 1-2
mM (in astrocytes it is 8 mM).
The CSF concentration of GSH is approximately 4 μM.
Neurons are highly dependent on astrocytes for their own
GSH synthesis.
20
GPx = glutathione peroxidase
Grx = glutaredoxin
GST = glutathione-S-transferase
GR = glutathione reductase
21
GCS = γ-glutamylcysteine synthetase
GS = GSH synthetase
ADP
ADP
ATP
ATP
GGT = γ-glutamil transpeptidase
ApN = aminopeptidase N
22
glia:
high glutamate
23
excitotoxicity:
24
Excitotoxicity (glutamate):
•ischemia
•stroke
•traumatic brain injury
•spinal cord injury
•epilepsy
•hypoglycemia
•Alzheimer's disease
•Huntington’s disease
•Parkinson’s disease
•amyotrophic lateral sclerosis
classical excitotoxicity
slow excitotoxicity
25
ΔpH = 0,75-1,4
ΔΨ = 0,15-0,2 V
26
In addition to ATP synthesis, mitochondria are the site of other
important metabolic reactions. Furthermore:
1) mitochondrial ROS are not just damaging by-products of
respiration, but important for cell signaling;
2) nitric oxide (NO) is a potent regulator of mitochondrial
function;
3) mitochondrial release of factors such as cytochrome c is an
important step in programmed cell death;
4) mitochondria actively orchestrate the spatiotemporal
profiles of intracellular Ca2+, under both physiological and
pathological conditions.
27
28
UP, Ca2+ uniporter
RaM, rapid-mode Ca2+ uptake
RyR, ryanodine receptor
PTP, permeability transition pore
ruthenium red
29
30
mitochondrial permeability transition pore (mPTP)
•voltage-dependent
anion channel
(VDAC, porine)
•adenine nucleotide
translocator (ANT)
•hexokinase (HK)
•creatine kinase (CK)
•cyclophilin D (CyD)
•peripheral
benzodiazepine
receptor (PBR)
•inner (IM) and outer
(OM) mitochondrial
membranes
31
consequences of mPTP opening:









disruption of metabolic gradients
mitochondrial osmotic swelling
mitochondrial depolarization
dissipation of the proton motive force
uncoupling of oxidative phosphorylation
ATP depletion
increased generation of ROS
mitochondrial Ca2+ efflux
release of cytochrome c and other apoptogenic proteins
32
the physical mechanism of cytochrome c release is still debated
33
has mPTP a role in normal mitochondrial physiology?
“permeability transition”:
34
O2 ●¯ + O2 ●¯ + 2 H+
reazione di Fenton:
Fe2+
H2 O2 + O2
OH● + OH¯ + Fe3+
+ H2 O2
reazione di Haber-Weiss: O2●¯ + H2O2
O2●¯ + NO
OONO¯ + H+
OONOH
OH● + OH¯ + O2
OONO¯ (perossinitrito)
OONOH (acido perossinitroso)
OH● + NO2●
35
ROS generation may increase in mitochondria when:
 substrate supplies are in excess
 the terminal electron acceptor O2 is abnormally low (hypoxia,
ischemia)
The generation of ROS is exponentially dependent on Δψm
Uncouplers decrease mitochondrial ROS generation
Ca2+ may be an important cause of mitochondrial ROS generation
36
Rot = rotenone
AntA = antimycin A
Myx = myxothiazol
mitochondrial reactive oxygen species (ROS) generation
calcium ionophore A23187 increases ROS generation
ruthenium red or calcium chelators inhibit ROS generation
37
 GSH
 ATP
 Δψ
Ca2+ overload may be an important cause of mitochondrial ROS generation
opening of the mPTP
cytochrome c dissociation
cardiolipin peroxidation
decreased electron transport
faster respiratory chain activity
38
neuron:
many calcium-dependent enzymes are activated
39
(two-hit hypothesis)
The reciprocal interactions between Ca2+-induced ROS increase and
ROS modulated Ca2+ upsurge may cause a feed-forward, self-amplified
loop creating cellular damage far beyond direct Ca2+ induced damage
40
polyADP-ribose polymerase (PARP)
41
42
NADP+ , GSH , GAPDH 
43
antioxidants, PARP inhibitors or PARP genetic knockouts prevent excitotoxicity
 glutamate
44
“ischemia/reperfusion”:
45
O2
anaerobic
glycolysis
Na+/K+-ATPase
lactate
pH
[Na+]i
NOX-2
mPTP
[Ca2+]i
ATP
ipoxanthine
XOR  XOD
Ca2+-ATPase
46
O2
ATP
Na+
ATP
O2
NOX
NO + O2●¯
XOD
O2●¯ + Fe-S
ROS
mPTP
futile
cycles
SOD
O2●¯
respiration
H2 O2
inib. resp., OH●
ONOO¯
H2O2, O2●¯, OH●
Fe2+
OH●
47
leukocytes activation
expression of adhesion molecules
formation of proinflammatory mediators   ROS
release of hydrolytic enzymes
Ca2+
mPTP
ROS
48
severe excitotoxic insult
mild excitotoxic insult
49
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