Title: Dopamine and cAMP-Regulated Phosphoprotein 32 kDa Controls Both Striatal Long-Term Depression and Long-Term Potentiation, Opposing Forms of Synaptic Plasticity

Authors: Paolo Calabresi,

Paolo Gubellini,

Diego Centonze,

Barbara Picconi,

Giorgio Bernardi, K

arima Chergui,

Per Svenningsson,

Allen A. Fienberg, and

Paul Greengard

Journal: Journal of Neuroscience

Year: 2000

The authors provide evidence that "the D1-like receptor-dependent activation of DA and cyclic adenosine 3',5' monophosphate-regulated phosphoprotein 32 kDa is a crucial step for the induction of both long-term depression (LTD) and long-term potentiation (LTP) ..."
"Formation of LTD and LTP requires the activation of protein kinase G and protein kinase A in striatal projection neurons. These kinases appear to be stimulated by the activation of D1-like receptors in distinct neuronal populations."

"... both nigral DAergic inputs and cortical glutamatergic terminal converge on the same striatal neuronal subtype, the spiny projection neuron, which represents >90% of the striatal cell population and is the only cell type projecting out of the striatum.
"Medium spiny neurons contain both D1-like (D1, D5) and D2-like (D2, D3, D4) DA receptors and also express both NMDA and non-NMDA classes of ionotropic glutamate receptors."
"In the striatum, D1- and D2-like receptors trigger opposite effects on intracellular levels of cAMP, stimulating and inhibiting adenylyl cyclase activity."
The activity of cAMP-dependent PKA is modulated by adenylyl cyclase activity.

A major PKA substrate is cyclic adenosine 3',5' monophosphate-regulated phosphoprotein 32 kDa (DARPP-32)
"DARPP-32 is expressed in very high concentrations in virtually all spiny neurons and acts (?), in its phosphorylated but not dephosphorylated form, as a potent inhibitor or protein phosphatase-1 (PP-1). PP-1 regulates the phosphorylation state and activity of many physiological effectors, including NMDA and AMPA glutamate receptors."

Aim: "The aim of the present study was to address how the concomitant activation of ionotropic glutamate receptors and D1-like DA receptors initiates a cascade of biochemical events leading to the formation of opposing forms of corticostriatal plasticity, namely, LTD and LTP"

No significant difference in the resting membrane potential, input resistance, and current-voltage relationship in neurons recorded from the two groups of animals.
AMPA receptor antagonist CNQX suppressed EPSPs in both sets of animals.

Removal of Mg$^{2+}$ (removes the voltage dependent block of NMDA receptors) was needed to reveal an NMDA component of the EPSP that could be block by APV (?)

Three spike trains of 100 Hz frequency, 3 s duration with 20 sec ISI of CORTICOSTRIATAL fibers produced 'long-term' chagnes in the AMPLITUDE of EPSPs in wild-type mice.

This caused LDP in the presence of Mg$^{2+}$ and LTP in the absence of Mg$^{2+}$
When knockout mice were given the same stimulation they show neither LTP nor LDP -> DARPP/PP-1 is necessary for AMPA's LT/DP related activity.
Direct test of whether inability to inhibit PP-1 is what causes lack of plasticity

Perform the same experiment and then bath the brain in okadaic acid and calcyculin A (PP-1 inhibitors)

Testing the blockade of D1-like DA receptors was effective in block both forms of learning.

D1-like DA receptor antagonist SCH 23990 prevented LTD and LTP in wild-type mice.

Next in the cascade is PKA induced phosphorylation of DARPP-32 so let's inhibit that

Intracellular injection of H89 (PKA inhibitor) block LTP but not LTD in wild-type mice.
However, when this was added to the Mg$^{2+}$ solution both forms of learning were prevented.
Suggests different cellular loci for PKA action on learning

For LTP but not for LTD this particular pathway is activated POST-synaptically on spiny neurons.

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