Download Afferents of dopamine neurons

The complexity and simplicity of dopamine neurons
J. Paul Bolam
MRC Anatomical Neuropharmacology Unit
Oxford
The normality, complexity, simplicity and
subtlety of dopamine neurons
J. Paul Bolam
MRC Anatomical Neuropharmacology Unit
Oxford
The complexity and simplicity of dopamine neurons
Organisation of dopamine neurons at level of SNC
(normality)
Projections of dopamine neurons (complexity)
Responses of dopamine neurons (simplicity)
The effects of dopamine neurons (subtlety)
Dopamine neurons in SNC
DAT immunolabelling
SNC
SNR
TH immunolabelling
Dopamine neurons in SNC
Bentivoglio and Morelli (2005) Handbook Chem. Neuroanat 21:1-107
Single cell labelling
Afferents of dopamine neurons
GABAergic afferents
Striatum
Globus pallidus
Substantia nigra reticulata
Afferents of dopamine neurons
GABA
GABAergic afferents
TH
Striatum
Globus pallidus
TH
Substantia nigra reticulata
GAD
Afferents of dopamine neurons
GABAergic afferents
Striatum
Globus pallidus
Substantia nigra reticulata
Fujiyama, Stephenson and Bolam (2002) Eur. J. Neurosci. 15:1961-1975
Afferents of DA
neurons
GABAergic afferents
Striatum
Globus pallidus
SNR
GABA and GABAA receptors
Afferents of DA
neurons
GABAergic afferents
Striatum
Globus pallidus
SNR
GABA and GABAA receptors
Afferents of dopamine neurons
GABAB receptors
GABAergic afferents
Striatum
Globus pallidus
Substantia nigra reticulata
Boyes and Bolam (2003) Eur. J. Neurosci. 18:3279-3293
Afferents of dopamine neurons
GABAergic afferents
GABAB receptors
Striatum
GP
SNR
Boyes and Bolam (2003) Eur. J. Neurosci. 18:3279-3293
Afferents of dopamine neurons
Glutamatergic afferents
Subthalamic nucleus
Pedunculopontine
nucleus
Cortex
Amygdala
Afferents of dopamine neurons
Glutamatergic afferents
VGLUT 2
STN
PPN
Cortex
Amygdala
Afferents of dopamine neurons
Glutamatergic afferents
STN
PPN
Cortex
Amygdala
Chatha, Bernard, Streit and Bolam, (2000) Neuroscience 101:1037-1051.
Afferents of dopamine neurons
Glutamatergic afferents
STN
PPN
Cortex
Amygdala
Chatha, Bernard, Streit and Bolam, (2000) Neuroscience 101:1037-1051.
Afferents of dopamine neurons
Glutamatergic afferents
STN
PPN
Cortex
Amygdala
Bolam, Francis and Henderson (1991) Neuroscience 41:483-494
Ross, Mena-Segovia, Magill and Bolam unpublished
Afferents of dopamine neurons the
substantia nigra pars compacta
Superior colliculus
5-Hydroxytryptamine: Raphe
Noradrenaline: LC
Peptides
Dopamine
Afferents of dopamine neurons the
substantia nigra pars compacta
SUMMARY
Dopamine neurons receive a complex
afferent innervation mainly from
GABAergic and glutamatergic terminals
Ionotropic GABAA and glutamate
receptors are mainly located at synapses
Metabotropic receptors are located at
synapses and extrasynaptic sites
GABAergic innervation mainly from
St, GP and SNR
Glutamatergic innervation mainly from
STN and PPN
Other functionally important afferents
The complexity and simplicity of dopamine neurons
Organisation of dopamine neurons at level of SNC
(normality)
Projections of dopamine neurons (complexity)
Responses of dopamine neurons (simplicity)
The effects of dopamine neurons (subtlety)
Projections of dopamine neurons
Striatum
GP
SNC
SNR
DAT immunolabelling
Projections of dopamine neurons
Striatum
GP
DAT immunolabelling
Striatum
Globus pallidus
The projections of
dopamine neurons
Topography of the projection
medial to lateral/limbic to motor
Dorsal and ventral tier
Striatonigral projection
patch and matrix
Based on retrograde and
anterograde labelling
Bentivoglio and Morelli ( 2005) Handbook Chem. Neuroanat 21:1-107
The projections of
dopamine neurons
Information flow from
frontal cortex through
the striatonigral circuit
Haber, et al., 2000 J. Neurosci.
The projections of dopamine neurons
Data from a variety of sources
including immunocytochemistry and
single cell filling indicate that
dopaminergic neurons innervate
other regions of basal ganglia
GPe Rodrigo et al 1998
Smith & Kieval 2000
Gauthier et al 1999
Prensa & Parent 2001
The projections of dopamine neurons
Data from a variety of sources
including immunocytochemistry and
single cell filling indicate that
dopaminergic neurons innervate
other regions of basal ganglia
GPe Rodrigo et al 1998
Smith & Kieval 2000
Gauthier et al 1999
Prensa & Parent 2001
The projections of dopamine neurons
GPe contains DAT-positive axons and boutons
Striatum
GP
Prime, Boyes, Magill and Bolam unpublished
The projections of dopamine neurons
TH immunolabelling
Rodrigo et al 1998; Prime, Boyes, Magill and Bolam unpublished
The projections of dopamine neurons
STN contains TH-positive and DA-positive axons and boutons
Cragg, Baufreton, Xue, Bolam & Bevan 2004 Eur. J. Neurosci. 20:1788-802
The projections of dopamine neurons
DA is released from STN upon electrical stimulation
Cragg, Baufreton, Xue, Bolam & Bevan 2004 Eur. J. Neurosci. 20:1788-802
The projections of dopamine neurons
DA affects the firing of STN neurons
Cragg, Baufreton, Xue, Bolam & Bevan 2004 Eur. J. Neurosci. 20:1788-802
The projections of dopamine neurons
In addition to innervation of the striatum, dopamine
neurons innervate other regions of the basal ganglia
Loss of dopamine at the level of the GP and/or the STN
may account for some of the changes in Parkinson’s
disease
Degree of collateralization of individual neurons?
Single cell filling studies
The projections of dopamine neurons
Small deposits of
anterograde tracer
in SNC
Single axons traced to
forebrain
Characterize the axonal
arborization of single
neurons
Respect patch matrix
Prensa and Parent (2001) J Neurosci 21:7247-7260
The projections of dopamine neurons
Several classes of neurons
based on location and
projection
Poor respect for the patch/
matrix organisation
High degree of
collateralization
Problems with the technique
DA or not
size of arborization
Based on quantitative
anatomical data the
arborization of a single
dopamine neuron is massive
Prensa and Parent (2001) J Neurosci 21:7247-7260
The projections of dopamine neurons
Number of synapses formed by dopamine neurons
15000 spines per spiny neuron (Wilson)
4% of spines receive symmetrical synapses (Wilson)
Assume half are dopamine terminals and half of dopamine terminals are on
spines
7.2 x 103 dopamine neurons in SNC (Oorschott)
2.78 x 106 spiny neurons in striatum(Oorschott)
THEREFORE
15000 x 0.02 x 2 x 2.78 x 106 / 7.2 x 103= 231 x 103 synapses per neuron
Freund et al 40% spines receive dopamine input which accounts for
60% of terminals
THEREFORE
15000 x 0.4 x 2.78 x 106 / 7.2 x 103 +40% = 3.24 x 106 synapses per neuron
369,881
Wickens and Arbuthnott (2005) Handbook Chem. Neuroanat 21:199-236
Neurons of the globus pallidus
Kita and Kitai (1994) Brain Res, 636, 308-309
Bevan, Booth, Eaton, and Bolam. (1998) J. Neurosci. 18, 9438-9452
The complexity and simplicity of dopamine neurons
Number of synapses formed by globus pallidus neurons
Striatum
GP
SNR
SNC
EP
STN
790
264 or 581
36-209
11-28
approx 100
41-274
Total Max around 1982 synapses per neuron
Kita and Kitai (1994) Brain Res, 636:308-309
Bevan, Booth, Eaton, and Bolam. (1998) J. Neurosci. 18: 9438-9452
Sadek, Magill and Bolam unpublished
The complexity and simplicity of dopamine neurons
Number of synapses formed by striatal neurons
around 300 synapses per neuron
Data from:
Kawaguchi et al 1990 J. Neurosci. 10:3421-3438
Wu et al 2000 Neurosci Res 38:49-62
PV-positive GABAergic interneuron
Approx. 5000 boutons
Tepper and Bolam (2004 ) Current Opinion Neurobiol.
The complexity and simplicity of dopamine neurons
Individual dopamine neurons give rise to a massive
number of synapses in the striatum
Non-synaptic release sites, collaterals to other regions
Difficulties of ‘control’ of the whole arborization
(branch point failures, local control of release at level of terminals,
metabolic support for such a large arborization)
Different to other neurons in the basal ganglia
The complexity and simplicity of dopamine neurons
Juxtacellular labelling of individual
dopamine neurons in vivo, chemical
characterisation and re-construction
Quantitative data on degree of
collateralization, numbers of
synapses formed and the nature and
pattern of innervation of their
postsynaptic targets
Boyes, Magill and Bolam unpublished
Ungless, Magill and Bolam 2004 Science 30:2040-2042
The complexity and simplicity of dopamine neurons
Organisation of dopamine neurons at level of SNC
(normality)
Projections of dopamine neurons (complexity)
Responses of dopamine neurons (simplicity)
The effects of dopamine neurons (subtlety)
Activity of dopamine neurons
The complexity and simplicity of dopamine neurons
Organisation of dopamine neurons at level of SNC
(normality)
Projections of dopamine neurons (complexity)
Responses of dopamine neurons (simplicity)
The effects of dopamine neurons (subtlety)
Spiny projection neurons
Major target of the nigrostriatal projection
Freund, Powell & Smith (1984)
The complexity and simplicity of dopamine neurons
Major target of dopamine
terminals is the spines of MSNs
Modulate the flow of cortical
information
Also innervate striatal
interneurons
Actions mediated through at
least two classes of receptors
Smith, Bennett, Bolam, Parent and Sadikot (1994) J. Comp. Neurol. 344:1-19
The complexity and simplicity of dopamine neurons
Dopamine receptors located at synaptic and
extrasynaptic sites
Technical issues relating to receptor
immunolabelling
Yung, Bolam, Smith, Hersch, Ciliax & Levey (1995). Neuroscience. 65 :709-730
The complexity and simplicity of dopamine neurons
Dopamine system is so remarkable
because of the plasticity of the
corticostriatal synapse
Dopamine modulates the flow of
cortical information
Plasticity of the corticostriatal
synapse is often dependent on
dopamine
Brought about by a variety of
mechanisms including LTP, LTD,
changes in excitability, receptor
interactions, signalling pathways
and gene regulation
1
2
3
4
5
6
7
Figure 4. Effect of dopamine on corticostriatal synapses. Effect of dopamine on activitydependent synaptic plasticity in the corticostriatal pathway. A. A conjunction of cortical
presynaptic activity and striatal postsynaptic activity, leads to long-term depression (LTD) in the
absence of a dopamine pulse. B. A conjunction of cortical presynaptic activity and striatal
postsynaptic activity, leads to long-term potentiation (LTP) if preceded by a dopamine pulse. C.
The same conjunction of cortical presynaptic activity and striatal postsynaptic activity, leads to
LTD if the dopamine pulse is delayed.
Bolam, Bergman, Graybiel, Kimura, Plenz, Seung, Surmeier, and Wickens (2005) In press.
The complexity and simplicity of dopamine neurons
Dopamine neurons have a complex organisation and afferent input
at level of SNC (normality)
The projections of dopamine neurons are extremely complex and
massive (complexity)
Responses of dopamine neurons are relatively simple and uniform
(simplicity)
The effects of released dopamine at the level of the striatum (other
regions of BG/ctx) are subtle and complex and enable dopamine to
have profound effects on behaviour (subtlety)
The challenge we have set ourselves in DOPANET is to understand
one of the most complex neurons in the brain and one of the most
complex neurotransmitters
The complexity and simplicity of dopamine neurons
Thanks to:
Peter Magill
Yoland Smith
Justin Boyes
Mark Ungless
Fumino Fujiyama
Tracey Chatha
Hana Ross
Juan Mena-Segovia
Mark Bevan
Stephanie Cragg
Bolam, Bergman, Graybiel, Kimura, Plenz, Seung, Surmeier, and Wickens (2005) In press.