Embed Size (px)
Citation preview
Receptorarchitecture and Neural Systems
Karl Zilles
Institute of Neuroscience and Medicine INM-1
Research Centre Jülich and
University Hospital of Psychiatry, Psychotherapy and
Psychosomatics
RWTH Universität Aachen
m
Transmitter Systems
Glutamate (ubiquitous;
excitatory)
GABA (ubiquitous;
inhibitory)
Acetylcholine (basal forebrain
Ch1 Septum
Ch2 vertical band
Ch3 horizontal b.
Ch4 NbM)
Dopamine (substantia nigra,
ventral tegmental
area VTA)
Noradrenaline (locus coeruleus)
Serotonin (raphe nuclei)
medial forebrain bundle
Receptors are protein complexes in the cell
membrane, to which transmitters selectively bind.
ionotropic receptors have an integrated ion channel
and regulate ion fluxes between extra- and intracellular space
metabotropic receptors are linked to intracellular
second messenger systems, and control metabolic
pathways, ion channels, gene activity, etc.
R
Example: Ionotropic Transmitter Receptors
postsynaptic
ionotropic
receptor
transmitter
ion channel
postsynaptic
membrane
presynaptic
ionotropic
receptor
presynaptic
membrane
axonal bouton
Adenosin A1 D1, D2, D4
D1, D2, D4
Dopamine
AMPA, NMDA, kainate
AMPA, NMDA, kainate
AMPA, NMDA, kainate
AMPA, NMDA, kainate
Glutamate
GABAA, bz.binding site
GABAA, bz.binding site
GABAA, bz.binding site
GABAA, bz.binding site
GABAB
GABAB
GABAA, bz.binding site
GABAB
GABA
nicotinic, M1, M2, M3
nicotinic, M1, M2, M3
Acetylcholine
a1, a2
a1, a2
Noradrenaline
5-HT1A, 5-HT2
5-HT1A, 5-HT2
Serotonin
How to map receptor distributions:
• in vivo receptor PET
• in vitro quantitative receptor autoradiography
• immunohistochemistry of receptor proteins and subunits
• transcriptomics
HG05/00
Sulcus
centralis
slab 2
native
slab 2
frozen
at -70° C
slab 2
Quantitative in vitro Receptor Autoradiography: Method (1)
Gyrus
praecentralis
Serial sections (20 µm) mounted onto glass slides
• Preincubation: re-hydrate sections. Remove endogenous
substances
• Main incubation: buffer solution with [3H]-ligands which
specifically bind to a given receptor type
• Washing step: stop binding procedure. Eliminate surplus
[3H]-ligand and buffer salts
Binding protocol
Total and nonspecific binding
Specific binding = total binding – nonspecific binding
Total binding
[3H]-ligand (nM)
Nonspecific binding
[3H]-ligand (nM) + displacer (µM)
Image processing
0
50
100
150
200
250
0 150000 350000
Receptor density
(fmol/mg protein)
Gre
y v
alu
es
Linearised autoradiograph
grey values
code
receptor densities
5-HT1A
M2 receptor
[3H] oxotremorine-M
184 fmol/mg protein
262 341 420
Myelin staining
Primary visual cortex
* *
Gennari‘s stripe
V2
V2
V1
V1
Myelin
vertical
meridian
vertical
meridian
GABAA Receptor
V2
V2
V1
V1
vertical
meridian
Sulcus
calcarinus
Zilles, K., Palomero-Gallagher, N. , Schleicher, A.: Transmitter receptors and functional anatomy
of the cerebral cortex. J. Anat. 205: 417-432 (2004)
vertical
meridian
Entorhinal-Hippocampal System
sub CA1
mol
CA2
fimbria
CA3
Kainate NMDA
AMPA
perforant path
mossy fibres
Schaffer collateral
CA1
mol
CA1
mol CA3 CA2
Glutamatergic terminals of
the perforant path and the
Schaffer collaterals
Glutamatergic terminals of the mossy fibers
Glutamatergic terminals of the perforant path
and the Schaffer collaterals
295 464 633 802
221 357 493 629 417 632 486 1061 fmol/mg protein fmol/mg protein
fmol/mg protein
Primary Sensory Cortices
Macaque
Brain
Human
Brain
primary
somatosensory
cortex
low density high density
primary
auditory
cortex
motor
cortex
motor cortex sc
sc
Cholinergic muscarinic M2 receptor
primary
auditory
cortex
primary
somatosensory
cortex
Receptor Fingerprints
Dopamine
Acetylcholine
Serotonin
Glutamate
Noradrenaline GABA
Low
denisty
High
density
AMPA Kainate NMDA M1 M2 M3 nicotinic
a1 a2 GABAA 5-HT1A 5-HT2 D1 D2
Multimodal visualization of receptor organization
in human cerebral cortex
Zilles, K., Schleicher, A., Palomero-Gallagher, N., Amunts, K.:
Quantitative analysis of cyto- and receptorarchitecture of the human brain, pp. 573-602.
In: Brain Mapping: The Methods, 2nd edition (A.W. Toga and J.C. Mazziotta, eds.). Academic Press (2002)
A receptor fingerprint is…
AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
nACh
a1
a2
5-HT1A
5-HT2
D1
area 4
caudate
putamen
0
500
1000
1500
2000
2500
3000
Receptor Fingerprints
AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT2
D1
1000
2000
3000
Hippocampus
CA1-3
0
primary motor cortex
AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT2
D1
0
5-HT1A 5-HT1A 1000
2000
3000
What receptors tell us about laminar segregation and input-output relations
in the cerebral cortex
molecular layer I
outer granular layer II
inner granular layer IV
outer pyramidal layer III
inner pyramidal layer V
polymorphic layer VI
CYTOARCHITECTURE
thalamo-
cortical
input
cortico-
cortical
input
CONNECTIVITY SYNAPTIC DENSITY
cortico-
-cortical,
-striatal,
-thalamic,
-bulbar, and
-spinal
output
AM
PA
K
ain
ate
N
MD
A
GA
BA
A
GA
BA
B
BZ
750
100
850
75
1700
100
2200
100
3000
100
3500
100
V1 I
III
IVa
IVb
IVc V VI
PFm 44d I II
IIIab
IIIc IV
V
VI
47 4d pSTG
/ STS
IFS1
/ IFJ 45 I II IIIab IIIc IV
V
VI
I II
IIIc IV
V
VI
I II
IIIc IV V
VI
I II
IIIc
V
VI
I II
IIIc IV
V
VI
I II
IIIc IV
V
VI
IIIab IIIab IIIab IIIab IIIab
II
PFm
47
IFS1/IFJ
45 pSTG/STS
44d
4d
V1
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT1A
5-HT2
D1
L. I
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT1A
5-HT2
D1
Ll. II-III
Receptor Fingerprints of the primary visual cortex: layer specificity
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT1A
5-HT2
D1
L. IV
L. V
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT1A
5-HT2
D1 L. VI
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
a1
a2
5-HT1A
5-HT2
D1
7
47
IFS1/IFJ 9
45p
44v 46 PFop
PFt
PFcm
PFm
PF
pSTG/STS
4d
44d
3b
Te1
Te2 45a
PGa PGp
4v
V1
FG1 FG2
32
Sentence comprehension-related and non-related brain regions
15 transmitter receptor types and cognitive systems
K. Zilles, M. Bacha-Trams, N. Palomero-Gallagher, K. Amunts, A.D. Friederici (2015). Common
molecular basis of the sentence comprehension network revealed by neurotransmitter receptor
fingerprints. Cortex 63: 79-89
fMRI defined regions “sentence comprehension task”
Euclidean Distance
0.5 1 1.5 2 2.5 3
FG2
FG1
PGp
Te2
PFt
PFop
PFcm
PGa
7
PFm
PF
pSTG/STS
IFS1/IFJ
45p
45a
44v
44d
32
9
46
47
4d
4v
V1
Te1
3b
Euclidean Distance
0.5 1 1.5 2 2.5 3
FG1
FG2
7
9
46
32
44v
44d
47
45a
pSTG/STS
Te2
45p
IFS1/IFJ
4v
4d
3b
Te1
V1
PF
PFm
PGa
PFcm
PFop
PFt
PGp
Left hemisphere
(language dominant side) Right hemisphere
multimodal
association
primary
sensory
language
network
multimodal
association
K. Zilles, M. Bacha-Trams, N. Palomero-Gallagher, K. Amunts, A.D. Friederici (2015). Common
molecular basis of the sentence comprehension network revealed by neurotransmitter receptor
fingerprints. Cortex 63: 79-89
Cluster analysis of the human cingulate cortex:
A multi-region model based on receptor fingerprints
Palomero-Gallagher, N., Vogt, B.A.,
Schleicher, A., Mayberg, H.S., Zilles, K. (2009) Receptor architecture of human cingulate cortex:
Evaluation of the four-region neurobiological
model.
Human Brain Mapping 30: 2336-2355
Eu
cli
de
an
dis
tan
ce
(W
ard
lin
ka
ge
)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
23d
23c
31
d23
v2
3
30
29l
29m
24a
24b
24cv
24cd
32
p2
4a
'
p2
4b
'
24
dv
24d
d
24
c'v
24
c'd
32'
25
a2
4b
'
a24a'
33
24a
24b
24cv
24cd
32
p2
4a
'
p2
4b
'
24
dv
24d
d
24
c'v
24
c'd
32'
25
a2
4b
'
a24a'
33
25
33
RSC
ACC
MCC
PCC aMCC pMCC
emotion
decision
motor
control
visuo-
spatial
attention
memory
limbic
memory
au
ton
om
ic
co
ntr
ol
Institute of Neuroscience and
Medicine (INM-1),
Research Centre Jülich
Katrin Amunts
Mareike Bacha-Trams
Svenja Caspers
Nicola Palomero-Gallagher
Axel Schleicher
Thanks to:
