Catecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness.
Both dopamine (DA) and norepinephrine (NE) have powerful, inverted U influences on prefrontal cortical (PFC) cognitive function. Optimal NE levels engage alpha2A-adrenoceptors and increase "signals" via inhibition of cAMP-HCN (cAMP-hyperpolarization-activated cyclic nucleotide-gated cation channel) signaling near preferred inputs, whereas optimal levels of DA D1 receptor stimulation decrease "noise" by increasing cAMP signaling near nonpreferred inputs. Excessive levels of catecholamine release during stress impair working memory 1) by very high levels of cAMP-HCN signaling diminishing preferred as well as nonpreferred inputs and 2) by high levels of NE engaging alpha1 stimulation of phosphotidyl inositol (PI) signaling that suppresses cell firing. Common mental illnesses are associated with extracellular changes in these pathways: Attention Deficit Hyperactivity Disorder is linked to genetic changes that reduce catecholamine transmission to suboptimal levels and is treated with agents that increase catecholamine transmission, whereas Post-Traumatic Stress Disorder (PTSD) is associated with amplified noradrenergic transmission that impairs PFC but strengthens amygdala function. PTSD is now treated with agents that block alpha1 or beta adrenoceptors. In contrast, the more severe mental illnesses, schizophrenia and bipolar disorder, are associated with genetic changes in molecules regulating intracellular signaling pathways activated by stress. Specifically, DISC1 inhibits cAMP signaling whereas regulator of G-protein signaling 4 inhibits PI signaling. Loss of function in these genes may render patients vulnerable to profound stress-induced PFC dysfunction including symptoms of thought disorder.
Arnsten
Amy F T
AF
Department of Neurobiology, Kavli Institute of Neuroscience, Yale Medical School, New Haven, CT 06510, USA. amy.arnsten@yale.edu
D000818:Animals; D001143:Arousal / Q000502:physiology; D002395:Catecholamines / Q000235:genetics* / Q000502:physiology*; D003712:Dendrites / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D001523:Mental Disorders / Q000235:genetics* / Q000503:physiopathology*; D009415:Nerve Net / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D015290:Second Messenger Systems / Q000235:genetics* / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology / Q000523:psychology
D002395:Catecholamines