A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes.
While stressful life events confer increased risk for the development of psychopathology, most individuals experiencing adversity maintain normal psychological functioning, suggesting that individual differences may influence the susceptibility to develop stress-related psychiatric disorders. However, little is known about what determines this difference between individuals at the molecular level. In the present study, we identify that protein tyrosine phosphatase nonreceptor type 5 (PTPN5) (also known as STEP) is a critical determinant of differences in individual susceptibility to develop stress-related cognitive and morphological changes in rats. Our data demonstrate that ablation of PTPN5 expression delays physiological recovery from stress and augments the development of stress-related cognitive and morphological changes, whereas overexpression of a constitutively active variant of PTPN5 enhances the individual's resilience to stress. Our data also reveal that reduced PTPN5 expression prolongs the duration of extracellular signal-regulated kinase activation, leading to an elevation of Ca(V)1.2 channel expression and a recovery delay of K(V)4.2 channels from inactivation, which in turn heightens neuronal vulnerability to glutamate toxicity. Moreover, intraperitoneal injections of L-type Ca(2+) channel blocker nifedipine after stress resulted in a significantly lower rate for developing stress-related cognitive and morphological changes seen in PTPN5 knockdown rats. Together, these results identify a novel role for PTPN5 in mediating the development of stress-related cognitive and morphological changes and suggest that people with PTPN5 deficiency may have a greater susceptibility to capture the deleterious effects of stress.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Chih-Hao
CH
Yang
Chiung-Chun
CC
Huang
Kuei-Sen
KS
Hsu
D000374:Aggression; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002461:Cell Line, Transformed; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology; D003216:Conditioning, Operant; D003345:Corticosterone / Q000097:blood; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D007206:Individuality; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000378:metabolism; D016622:Silver Staining; D013315:Stress, Psychological / Q000097:blood / Q000150:complications* / Q000473:pathology*; D013550:Swimming / Q000523:psychology; D013997:Time Factors
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051672:Shal Potassium Channels; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007770:L-Lactate Dehydrogenase; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D009543:Nifedipine; D003345:Corticosterone