Regulation of Neuronal Excitability by Calcium Release

Project: Research project

Project Details


DESCRIPTION (provided by applicant): The mesolimbic system, particularly the
dopaminergic neurons of the ventral tegmental area (VTA) play an essential role
in endogenous reward. Activation of the reward pathway is associated with
increased dopamine release brought about by an increase in the activity of VTA
dopaminergic neurons. The reinforcing actions of drugs of abuse such as opioids
and psychostimulants are mediated by increasing the activity of dopamine
neurons. A grasp of the mechanisms that regulate the excitability of these
cells, therefore, is essential for a better understanding of the cellular
mechanisms involved in endogenous reward and in drug addiction. Recently, it
has been shown that stimulation of glutametergic synaptic inputs result in a
slow hyperpolarization of VTA dopamine cells that requires the activation of
glutamate metabotropic receptors (mGluRs). It has been proposed that these
inhibitory postsynaptic potentials (IPSPs) are produced by activation of small
conductance calcium-dependent potassium channels (SK) by calcium release from
intracellular stores. Both of the two calcium release channels, the inositol
triphosphate (InsP3) and ryanodine receptors, have been implicated in this

The main goal of this proposal is to test the hypothesis that InsP3-evoked
calcium release, augmented by calcium-induced calcium release (CICR), mediates
the mGluR-dependent IPSPs in VTA dopaminergic cells. These experiments will be
done by combining whole-cell recordings from VTA dopaminergic neurons in
acutely prepared midbrain slices with calcium imaging. To mobilize calcium, all
second messenger cascades will be bypassed and InsP3 will be photoreleased into
the cytosol by flash photolysis of caged InsP3. The extent to which CICR
contributes to InsP3-evoked calcium transients will be evaluated by inhibition
of ryanodine receptors with selective antagonists. In addition, the extent to
which, and the mechanism by which, prior neuronal activity modulates the
mGluR-mediated IPSPs will be delineated.
Effective start/end date8/1/015/31/06


  • Psychiatry and Mental health
  • Medicine(all)
  • Neuroscience(all)


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