Afferent Regulation of Dopaminergic Neurons

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Afferent Regulation of Dopaminergic Neurons
The Role of GABAergic Inputs J.M. Tepper Rutgers
University
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• Most (70-90) of the synapses made onto
  substantia nigra dopaminergic neurons are
  GABAergic. Most of these derive from the output
  neurons of the striatum, globus pallidus and
  substantia nigra pars reticulata.
• Dopaminergic neurons express both GABAA and GABAB
  receptors.
• Dopaminergic neurons respond to local application
  of either GABAA- or GABAB-selective agonists with
  a strong hyperpolarization and inhibition of
  activity.

DA neuron
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pacemaker
random
bursty
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Which GABAergic inputs(s) are responsible for
modulating burst firing in vivo?
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Why is there such a difference in the effects of
GABAA receptor stimulation on the firing rates of
dopaminergic and GABAergic nigral neurons?
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Gulacsi, Lee, Sik, Viitanen, Kaila, Tepper, and
Freund, submitted
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Gulacsi, Lee, Sik, Viitanen, Kaila, Tepper, and
Freund, submitted
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KCC2 is present on GABAergic but not
dopaminergic nigral neurons
Gulacsi, Lee, Sik, Viitanen, Kaila, Tepper, and
Freund, submitted
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Gulacsi, Lee, Sik, Viitanen, Kaila, Tepper, and
Freund, submitted
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Which GABAergic inputs(s) are responsible for
modulating burst firing in vivo?
A least one important pathway is the
pallido-nigral pathway. Stimulation of this
pathway inhibits the reticulata projection
neurons, thereby disinhibiting the DA neurons and
allowing them to burst, although the mean firing
rate does not increase by very much.
Does modulation of this pathway affect striatal
DA levels in vivo, i.e., is there functional
significance of this effect with respect to
striatal dopaminergic transmission ?
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Striatal DA increased by gt 40 while firing rate
increased by only 11
5 minute samples
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How does GABAA receptor stimulation or blockade
modulate burst firing?
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How does GABAA receptor stimulation or blockade
modulate burst firing?
The decrease in input resistance seems to be the
most important event.
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What about the postsynaptic GABAB receptors?
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• Activation of GABAergic afferents by local
  electrical stimulation of substantia nigra or VTA
  in vitro evokes both GABAA and GABAB IPSPs in
  dopaminergic neurons.

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Why does activation of striatal, pallidal or pars
reticulata output neurons fail to activate GABAB
responses in vivo?

• Maybe the GABAB responses originate from some
  other GABAergic input.

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• Small neurons that fire a large proportion of
  their spikes in very high frequency bursts are
  sometimes encountered in pars reticulata in vivo.
  These may be GABAergic interneurons and could
  serve as a source of the input to GABAB receptors
  on dopaminergic neurons.

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Why does activation of striatal, pallidal or pars
reticulata output neurons fail to activate GABAB
responses in vivo?

• GABAB responses originate from some other
  GABAergic input.

• Maybe it has something to do with the location of
  the GABAB receptors.

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• It is often reported that GABAB responses in
  dopaminergic neurons are only seen following
  local stimulation in vitro when larger amplitudes
  or higher frequencies of stimulation are employed.

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• Substantia nigra dopaminergic neurons and
  dendrites stain heavily for the GABABR2 subunit.

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• At the EM level, the immunogold labeling in
  dendrites appears membrane bound but is not
  localized to the active zones of symmetric
  synapses and in fact seems to be largely
  constrained to extrasynaptic plasma membrane.

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• The gold particles are frequently located
  perisynaptically, appearing to form an annulus at
  the edges of the active zones of symmetric
  synapses.

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Summary and Conclusions

• Although nigral DA neurons express both GABAA and
  GABAB receptors, synaptic responses elicited in
  vivo by activation of striatal, pallidal or
  nigral pars reticulata projection neuron
  afferents are mediated predominantly or
  exclusively by GABAA receptors.

• The predominant role of nigral GABAB receptors in
  vivo is as a presynaptic inhibitory autoreceptor,
  modulating the release of GABA from striatal,
  pallidal and nigral reticulata afferents.

• Blockade of GABAA receptors on DA neurons
  produces burst firing that is similar or
  identical to endogenous burst firing and which is
  independent of changes in firing rate.

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Summary and Conclusions II

• Disinhibition of a tonic GABAergic input from
  pars reticulata neurons is an important mechanism
  for controlling the firing pattern of DA neurons
  in vivo and triggering burst firing. Inhibition
  from the GP is a prime contributor to the
  disinhibition. The modulation of burst firing
  itself appears to depend on GABAA
  receptor-mediated changes in membrane resistance.

• The failure to see GABAB-mediated synaptic
  responses in vivo may be due to an extrasynaptic
  location of the GABAB receptor on DA dendrites.
  This would require overflow of GABA from the
  synapse for activation of the receptor such as
  might occur with saturation of the GABA uptake
  mechanism due to high frequency synchronous
  activation of GABAergic inputs and/or compromise
  of the uptake mechanism.

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