Fleeting Thoughts: Molecular Vulnerabilities in Prefrontal Cortical Networks
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1
Yale University School of Medicine , United States
Prefrontal cortical pyramidal cells form networks that engage in recurrent excitation to maintain neuronal firing even in the absence of environmental stimulation. This persistent activity is thought to be the neural basis of representational knowledge, our “mental sketchpad”, and is mediated through glutamatergic stimulation of NMDA receptors. We have discovered that these prefrontal cortical network connections are dynamically regulated by molecular signaling cascades that open or close ion channels on spines near network synapses to rapidly and flexibly control the strength of network connections (Dynamic Network Connectivity; Arnsten et al., in press). Negative feedback mechanisms involving calcium and cAMP weaken network inputs to prevent over-excitability, e.g. by opening potassium channels that hyperpolarize the spine. This may prevent seizures and conserve energy during fatigue, but may limit working memory capacity. These signaling pathways are also commandeered during stress exposure when high levels of catecholamines drive cAMP production and take prefrontal cortex “off-line”, switching control of behavior to more primitive brain mechanisms. In contrast, there are opposing signaling cascades that inhibit cAMP signaling, strengthen network connections and enhance prefrontal cortical cognitive function during alert, interested attention. Genetic or environmental insults to these pathways are associated with cognitive disorders such as schizophrenia, ADHD, age-related cognitive decline and possibly some aspects of Alzheimer’s Disease. Understanding these powerful molecular mechanisms is critical for the intelligent development of drug treatments for cognitive disorders.
References
1. Arnsten. Nature Reviews Neuroscience, 2009, 32, 267-287
Conference:
The 20th Annual Rotman Research Institute Conference, The frontal lobes, Toronto, Canada, 22 Mar - 26 Mar, 2010.
Presentation Type:
Oral Presentation
Topic:
Symposium 1: Neuroanatomy & Neuropharmacology
Citation:
Arnsten
AF
(2010). Fleeting Thoughts: Molecular Vulnerabilities in Prefrontal Cortical Networks.
Conference Abstract:
The 20th Annual Rotman Research Institute Conference, The frontal lobes.
doi: 10.3389/conf.fnins.2010.14.00025
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Received:
25 Jun 2010;
Published Online:
25 Jun 2010.
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Correspondence:
Amy F Arnsten, Yale University School of Medicine, New Haven, United States, amy.arnsten@yale.edu