TY - JOUR
T1 - A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes
AU - Yang, Chih Hao
AU - Huang, Chiung Chun
AU - Hsu, Kuei Sen
PY - 2012/5/30
Y1 - 2012/5/30
N2 - 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 V1.2 channel expression and a recovery delay of K V4.2 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.
AB - 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 V1.2 channel expression and a recovery delay of K V4.2 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.
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U2 - 10.1523/JNEUROSCI.5902-11.2012
DO - 10.1523/JNEUROSCI.5902-11.2012
M3 - Article
C2 - 22649233
AN - SCOPUS:84861582718
SN - 0270-6474
VL - 32
SP - 7550
EP - 7562
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 22
ER -