Glucocorticoid effects on working memory impairment require l-type calcium channel activity within prefrontal cortex
Areg Barsegyan1, James L McGaugh2, Benno Roozendaal1
1Dept. Cognitive Neuroscience, Radboud university medical center, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands.
Neurobiology of Learning and Memory
|November 21, 2022
Summary
Glucocorticoids impair working memory by increasing l-type voltage-gated Ca2+ channel activity in the prefrontal cortex. This pathway involves the beta-adrenoceptor-cAMP-PKA signaling cascade, with channel activity being crucial for memory deficits.
Area of Science:
- Neuroscience
- Endocrinology
- Cognitive Science
Background:
- Glucocorticoid hormones are known to impair working memory.
- This impairment is linked to the beta-adrenoceptor-cAMP signaling cascade and increased protein kinase A (PKA) activity in the prefrontal cortex (PFC).
- The downstream cellular mechanisms by which PKA activation affects PFC cognitive function remain unclear.
Purpose of the Study:
- To investigate whether l-type voltage-gated Ca2+ channel (LTCC) activity in the PFC mediates the effects of glucocorticoids and PKA on spatial working memory.
- To elucidate the role of LTCCs in the prefrontal cortex during glucocorticoid-induced working memory impairment.
Main Methods:
- Male Sprague Dawley rats were used in a delayed alternation task in a T-maze.
- Bilateral administration of an LTCC inhibitor (diltiazem) or agonist (Bay K8644) into the PFC was performed.
- Drugs targeting the glucocorticoid receptor (RU 28362) and PKA (Sp-cAMPS) were co-administered with diltiazem.
Main Results:
- Both the glucocorticoid agonist RU 28362 and the PKA activator Sp-cAMPS impaired spatial working memory.
- The LTCC inhibitor diltiazem completely blocked the working memory impairments induced by RU 28362 or Sp-cAMPS.
- Administration of the LTCC agonist Bay K8644 alone was sufficient to impair working memory.
Conclusions:
- Glucocorticoids impair working memory by increasing LTCC activity in the PFC.
- This effect is mediated through the beta-adrenergic signaling cascade and enhanced PKA activity.
- LTCCs in the PFC are a critical downstream target for glucocorticoid-induced working memory deficits.
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