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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
NMDA Receptor: Transmitter Glutamate/Effect: Excitation
NMDA receptors are highly permeant for Ca2+, and the ion channel is blocked in a voltage- and use-dependent manner by physiological concentrations of Mg2+ ions. These properties make them ideally suited for Hebbian processes in synaptic plasticity such as learning.
Metabotropic Glutamate Receptors: Transmitter Glutamate/Effect: Excitation
Glutamate
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
α1, α2
α1, α2
Noradrenaline
5-HT1A, 5-HT2
5-HT1A, 5-HT2
Serotonin
Ionotropic glutamate AMPA receptor
Ionotropic glutamate NMDA receptor
Ionotropic glutamate Kainate receptor
Metabotropic glutamate mGluR 2/3 receptor
Metabotropic acetylcholine M2 receptor
Ionotropic glutamate GABAA receptor
• presynaptic • postsynaptic • autoreceptor • heteroreceptor
glutamate
acetylcholine
GABA
axon
axon
axon
dendrite
Inhibitory interneuron
Modulatory projection
neuron
Presynaptic excitatory pojection neuron
Postsynaptic Neuron
inhib/excit
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
Image processing
0
50
100
150
200
250
0 150000 350000
Radioactivity concentration (cpm)
Gre
y va
lues
Linearised and color-coded autoradiograph
grey values or colors encode
receptor densities
5-HT1A
LLK
SC D
a
+⋅=
1 [fmol/mg protein]
50
400
Regional Specificity (example: Amygdala)
and
Connectivity (example: Hippocampus)
muscarinic receptor M2 GABAA receptor NMDA receptor
basomedial basolateral
lateral
Amygdala
Receptor autoradiography
Structural MRI at 4 Tesla: spatial resolution 350 µm isotrop
bm bl l
sub
Kainate NMDA
AMPA
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
mol
pp
CA3
CA2
CA1
Schaffer collaterals
mf
Genetic cell typing by Weissman & Lichtman (2006)
Principal Cortical Organization
Example: Primary Sensory Cortices
Cholinergic muscarinic M2 receptor [3H] oxotremorine-M Myelin staining
184 fmol/mg protein
262 341 420
Matching receptor- and myeloarchitecture
* *
* V1
V1
V1
layers II-IVa
layer IVc
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
Human primary visual cortex V1
Macaque Brain
Human Brain
primary somatosensory cortex
primary auditory cortex
motor cortex
motor cortex sc
sc
Cholinergic muscarinic M2 receptor
primary auditory cortex
primary somatosensory cortex
184 fmol/mg protein 420
Multi-Receptor Fingerprints
Dopamine
Acetylcholine
Serotonin
Glutamate
Noradrenaline GABA
Low density
High density
AMPA Kainate NMDA M1 M2 M3 nicotinic
α1 α2 GABAA 5-HT1A 5-HT2 D1 D2
Multiple (multimodal) receptor organization in the 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)
Zilles, K., Palomero Gallagher, N.: Comparative analysis of receptor subtypes that identify primary cortical sensory areas. In (Kaas, J., Striedter, G., Krubitzer, L., Herculano-Houzel, S., Preuss, T., eds.) Evolution of the Nervous System. Elsevier, Oxford (in press)
α1 D1 5-HT2
* *
* *
*
V1
V2
low high
*
*
*
*
GABAA GABAB nic α4β2 M1
mGluR2/3 kainate NMDA AMPA V2
*
Human primary visual cortex
5-HT1A
A receptor fingerprint is… AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
nACh
α1
α2
5-HT1A
5-HT2
D1
area 4
caudate putamen
0
500
1000
1500
2000
2500
3000
3b
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
4
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
V1
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
41
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
Fingerprints: modality specificity primary somatosensory primary motor primary auditory
V2 V3
primary (V1), and higher (V2, V3) visual areas
Ventral visual stream in human extrastriate cortex (pFus)
(pFus)
FG1 FG2 (pFus) GABAB
GABAA bz b.s.
NMDA
5-HT1A
Receptor fingerprint of FG1
Receptor fingerprint of FG2
Caspers, J., Palomero-Gallagher, N., Caspers, S., Schleicher, A., Amunts, K., Zilles, K.: Receptor architecture of cytoarchitectonic visual areas FG1 and FG2 of the posterior fusiform gyrus. Brain Struct. Funct. 220: 205-220 (2015)
ventral stream
Hierarchical Cluster Analysis
auditory
somatosensory
motor
On the way to understand mechanisms behind receptor fingerprints: Conditional 5-HT1A receptor knockout
WT
KO
64 636 fmol/mg protein
5-HT1A receptor
109 1091 fmol/mg protein
α1 receptor
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
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
L. I
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
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
α1
α2
5-HT1A
5-HT2
D1
L. IV
L. V
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1 L. VI
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1 I II
IV
III
I II
III
V
VI
I II
IV
III
V
VI
In/output Synapse
Receptor Fingerprints
and
Complex Neural Systems
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”
AM
PA
Kai
nate
N
MD
A
GA
BA A
G
AB
AB
B
Z
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
Laminar distribution of
multiple receptors in different
cortical areas
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
multimodal association
primary sensory
language network
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)
multimodal association
Hierarchical Cluster Analysis of Multi-receptor Fingerprints Reveals Principles of Functional Organization
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
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
Right hemisphere
multimodal association
primary sensory
Broca‘s region
multimodal association
Hierarchical Cluster Analysis of Multi-receptor Fingerprints Reveals Principles of Functional Organization
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich: Katrin Amunts Mareike Bacha-Trams Julian Caspers Svenja Caspers Nicola Palomero-Gallagher Axel Schleicher Stanford University: Kalanit Grill-Spector Kevin Weiner MPI Leipzig: Angela Friederici UCLA, Ahmanson-Lovelace Brain Mapping Center: John C. Mazziotta, Arthur Toga
Thanks to:
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