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Persistence of Memory in the Frontal Cortex: Timely Roles for Glutamate and Dopamine

4 February 2009. Unlike long-term potentiation, which can take minutes or more to activate and is relatively persistent, or long-term memory, which also requires the formation of new proteins and connections between neurons, delayed afterpolarization (dADP) provides a new mechanism whereby single neurons sustain a depolarization in the absence of sustained input. An impressive body of work published in the February 1, 2009 issue of Nature Neuroscience by Donald Cooper of University of Texas Southwestern Medical Center, Dallas, Kyriaki Sidiropoulou of the Chicago Medical School, and colleagues describes dADP as a mechanism for high-turnover memory in single neurons. The authors suggest that alterations of this short-term persisting membrane depolarization might contribute to working memory or attention deficits in disorders like schizophrenia.

Using patch-clamp recording from slice cultures of rat limbic cortex, a model for the human prefrontal cortex, they showed that metabotropic glutamate receptor (mGluR) agonism with the compounds ACPD or DHPG induced a long-lasting increase in layer V pyramidal neuron depolarization in response to brief depolarizing stimuli. mGluR agonism did not change the few action potentials generated by the depolarizing stimulation, but generated far more subsequent action potentials, and a far higher membrane depolarization, than normal. These cortical changes were calcium dependent and sodium independent, were not prevented by AMPA or NMDA receptor antagonism, were mostly blocked by the mGluR5 receptor antagonist, MPEP, and were absent in mGluR5 knockout mice. Neither the selective mGluR1 antagonist, LY367385, nor the use of mGluR1 knockout mice, prevented this effect, ruling out the mGluR1 receptor. Group 2 mGlu receptors also did not play a role, as their antagonism with LY431495 did not prevent dADP in response to ACPD.

The greatest dopamine input in the frontal cortex is to layer V pyramidal neurons, which also contain 20-fold more D1 receptors than D2 receptors. D1 agonism with SKF81297 blocked dADP induced by mGluR5 activation, whereas D2 agonism with quinpirole did not. The ability of the D1 antagonist SCH23390, or the protein kinase A (PKA) blocker, H89, to block the SKF81297 effect, and the ability of the PKA activator, forskolin, to mimic the D1 agonist effect, demonstrated that a D1-mediated induction of PKA is one pathway through which dADP activation by glutamate can be attenuated.

While the enabling role of mGluR5 agonism and attenuating effects of D1 agonism on dADP were elegantly revealed in these comprehensive studies, some of the functional implications of these interactions are puzzling. For example, how are increases in dopamine release from ventral tegmental area (VTA) neurons during reward to be reconciled with D1 receptor-mediated decreases in dADP they observed? Such a pairing would seem to lessen behavioral responses to reward or decrease memory of the behavior-reward association. The well-known, inverted U-shaped relationship between D1 activation and prefrontal cortex memory function (see SRF related news story and SRF news story) seems to be opposite for the inhibitory role of D1 receptors in the dADP response to glutamate, unless in vivo dopamine tone is at a maximum. This tone may not be modeled in their in vitro slice preparation, however, since it severs VTA inputs. It was also unclear how the D1-mediated decrease in dADP would "increase the signal-to-noise ratio by selecting only the strongest synaptic inputs for persistent activation." Wouldn't a stronger dopamine release during stimulants or reward actually diminish glutamate-stimulated dADP?

Sidiropoulou and colleagues also showed that chronic cocaine treatment of rats decreased the ability of D1 agonism with SKF81297 to block dADP induction by DHPG. Remarkably, this in vivo compensation persisted for at least two weeks, when it was assessed ex vivo in their brain slice preparation. The result may provide a mechanism for how chronic stimulant use in humans contributes to poor decisions, impulsivity, and inattentiveness, particularly during withdrawal. Whether inverted U-shaped or not, the relationships between the D1 or mGluR5 mechanisms and the dADP response need to be characterized in cocaine-sensitized versus vehicle-treated rats. This may help determine if stimulant-based adaptations in dADP contribute to psychostimulant alterations in attention, executive function, addiction, and relapse.—C. Anthony Altar.

Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Sidiropoulou K, Lu FM, Fowler MA, Xiao R, Phillips C, Ozkan ED, Zhu MX, White FJ, Cooper DC. Nat Neurosci. 2009 Feb;12(2):190-9. Epub 2009 Jan 25. Abstract

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