A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory - PubMed (original) (raw)

Comparative Study

. 2005 Mar-Apr;12(2):103-10.

doi: 10.1101/lm.89405.

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Comparative Study

A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory

Jason D Runyan et al. Learn Mem. 2005 Mar-Apr.

Abstract

The prefrontal cortex is involved in the integration and interpretation of information for directing thoughts and planning action. Working memory is defined as the active maintenance of information in mind and is thought to lie at the core of many prefrontal functions. Although dopamine and other neurotransmitters have been implicated, the intracellular events activated by their receptors that influence working memory are poorly understood. We demonstrate that working memory involves transient changes in prefrontal G(q/11)-signaling and in calcium-dependent intracellular protein phosphatase and kinase activity. Interestingly, inhibition of the calcium activated phosphatase calcineurin impaired, while calcium/calmodulin dependent kinase II (CaMKII) and calcium-dependent protein kinase C (PKC) enhanced, working memory. Our findings suggest that the active maintenance of information required for working memory involves transient changes in the balance of these enzymes' activities.

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Figures

Figure 1.

Figure 1.

mPFC activity and D1 receptors are required for performance in a delay match-to-place working memory task. Average latency to hidden platform for location and match trials for animals infused into the mPFC with the following: (A) muscimol (0.5 μg), a GABA agonist; (B) SCH-23390 (1 μg), a D1/D5 receptor antagonist; (C) SKF-38393 (1 μg), a D1/D5 receptor agonist; and (D) SKF-38393 (0.08 μg) compared with their respective vehicle infused controls. (E) Working memory performance follows an inverted-U response curve to D1 receptor stimulation (expressed as the delta [Δ] latency between the location and match trials). (F) Average latency to hidden platform for location and match trials for animals infused into the hippocampus with SCH-23390 (1 μg). *P < 0.05 comparing location to match trials; †P < 0.05 comparing match trials between groups.

Figure 2.

Figure 2.

Spatial working memory involves PLC and calcineurin activities. (A) Representative Gq/11α and Na+/K+ ATPase Western blots performed on mPFC membrane extracts taken at time-points during the delay match-to-place task compared against swim controls. Summary results showing average Gq/11α immunoreactivity as a percentage of that obtained for swim controls. *P < 0.05. (B) Average latency to hidden platform for location trials and match trials during the delay match-to-place task for intra-mPFC infused vehicle and U73122 (0.26 μg). *P < 0.05 comparing location to match trials; †P < 0.05 comparing match trials between groups. (C) mPFC calcineurin activity expressed as percentage swim control at time-points during the delay match-to-place working memory task. *P < 0.05. (D) Average latency to hidden platform for location and match trials during the delay match-to-place task for intra-mPFC vehicle, and cyclosporin A (0.3 μg or 0.7 μg) animals. *P < 0.05 comparing location to match trials.

Figure 3.

Figure 3.

CaMKII activity negatively influences spatial working memory. (A) Representative confocal images of phospho-CaMKII (green) and NeuN (red) immunoreactivity of mPFC tissue sections taken from animals performing the working memory task (immediate) or from swim control. Phospho-CaMKII immunoreactivity was not detected in GFAP-expressing astrocytes (red) (B) or GAD67-expressing inhibitory neurons (C). Scale bar for all images = 10 μm. (D) mPFC CaMKII activity expressed as percent swim control at time-points during the delay match-to-place working memory task. (E) Average latency to hidden platform for location and match trials for intra-mPFC KN-93–infused (1 μg), a CaMKII inhibitor, or vehicle-infused animals. *P < 0.05 comparing location to match trials; †P < 0.05 comparing match trials between groups.

Figure 4.

Figure 4.

PKC activity negatively influences performance in the delay match-to-place task. (A) PKC activity expressed as percent swim control at time-points during the working memory task. Average latency to hidden platform for location and match trials for intra-mPFC. (B) GF109203X (1 μg), a PKC inhibitor, and (C) Gö6976-infused (1 μg), a Ca2+-dependent PKC inhibitor, animals compared with vehicle controls. (D) Illustration of coronal sections (3.2 mm and 3.7 mm to bregma) of the mPFC indicating the non-redundant infusion sites for the animals in this study. *P < 0.05 comparing location to match trials; †P < 0.05 comparing match trials between groups.

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