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This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and\/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and\/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without \u201cbottom-up\u201d sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP\u2013PKA\u2013calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP\u2013PKA signaling. Excessive levels of cAMP\u2013calcium signaling can have a number of detrimental effects: for example, opening nearby K\n                    <jats:sup>+<\/jats:sup>\n                    channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium\u2013cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium\u2013cAMP signaling and are associated with increased risk of schizophrenia (e.g.,\n                    <jats:italic>GRM3<\/jats:italic>\n                    ). Age-related loss of regulatory proteins which result in elevated calcium\u2013cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the \u201cgenie\u201d we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation.\n                  <\/jats:p>","DOI":"10.1038\/s41380-020-00973-3","type":"journal-article","created":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T03:03:18Z","timestamp":1608001398000},"page":"3684-3700","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3420-1308","authenticated-orcid":false,"given":"Amy F. 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