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, 32 (22), 7550-62

A Critical Role for Protein Tyrosine Phosphatase Nonreceptor Type 5 in Determining Individual Susceptibility to Develop Stress-Related Cognitive and Morphological Changes

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A Critical Role for Protein Tyrosine Phosphatase Nonreceptor Type 5 in Determining Individual Susceptibility to Develop Stress-Related Cognitive and Morphological Changes

Chih-Hao Yang et al. J Neurosci.

Abstract

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.

Figures

Figure 1.
Figure 1.
Individual difference in susceptibility for developing stress-related cognitive and morphological changes. A, Horizontal scatterplot depicting the distribution of discrimination index in the OLM performance before, 3 h after, and 1 week after stress. Although there were no differences in the average memory performance between nonstress (NS), prestress (Pre-S), and poststress-1 week (Post-S-1 wk) groups, only 20% (6 of 31) rats exhibited OLM impairment 1 week after stress. B, Graph representing the distribution of discrimination index for individual rats before and 1 week after stress. An increase or decrease in discrimination index by >20% was defined as a significant change in the OLM. C, In response to acute stress, only susceptible (SUS) but not unsusceptible (US) rats exhibited a significantly impaired OLM 1 week later. D, Horizontal scatterplot illustrating the distribution of dendritic spine density in hippocampal CA1 pyramidal cells in NS and S group rats. Although there were no differences in the average spine density between groups, 19% (6 of 31) rats exhibited spine loss after stress. E, In response to acute stress, only SUS rats exhibited a significant decrease in dendritic spine density 1 week later. F, Representative images showing the density of Golgi-impregnated hippocampal CA1 neuronal dendritic spines in NS, US, and SUS rats. Scale bar, 10 μm. G, Correlation analysis of the discrimination index in the OLM and the number of dendritic spines in hippocampal CA1 pyramidal cells at 1 week after stress procedure. *p < 0.05. N.S., Nonsignificant. Error bars indicate SEM.
Figure 2.
Figure 2.
The susceptible group of rats shows depressive-like behaviors and loss of dendritic spines 2 weeks after stress. A, Pie chart and bar graph showing the relative distribution of the OLM performance in susceptible populations by subtracting poststress values from prestress values at 1 or 2 weeks after stress procedure. The susceptibility was defined as index <80%. B, Pie chart and bar graph showing the relative distribution of dendritic spine density in hippocampal CA1 pyramidal cells of susceptible populations at 1 or 2 weeks after stress procedure. The number <45 per 50 μm was classified as susceptible. C, Summary of experiments showing the response in a two-bottle sucrose preference test in US and SUS rats at 1 or 2 weeks after stress procedure (n = 7 in each group). D, Summary of experiments showing the time spent immobile during the forced-swimming test in US and SUS rats at 1 or 2 weeks after stress procedure (n = 7 in each group). E, Plasma corticosterone concentration measured immediately before and after 5 min swimming stress (n = 7 in each group). The horizontal bar denotes the period of delivery of swimming stress (5 min). Each value in parentheses is the number of animals showing susceptibility relative to total number of animals examined. *p < 0.05. Error bars indicate SEM.
Figure 3.
Figure 3.
Correlation for the expression of PTPN5 in the hippocampus and the development of stress-related cognitive and morphological changes. A, Representative immunoblots and corresponding densitometric analysis showing PTPN5 protein expression in hippocampal CA1 region of NS, US, and SUS rats. B, Summary of experiments showing the PTPN5 activity in hippocampal CA1 tissue lysates from NS, US, and SUS rats (n = 6–11 in each group). C, Summary of experiments showing the expression screening for 11 brain-enriched protein tyrosine phosphatases in US and SUS rats at 1 week after stress procedure by quantitative real-time PCR (n = 4–5 in each group; #p < 0.05 compared with control rats; *p < 0.05 compared with US rats). D, Correlation analysis of the discrimination index in the OLM and PTPN5 protein expression in the hippocampus at 1 week after stress procedure. E, Correlation analysis of the number of dendritic spines in hippocampal CA1 pyramidal cells and PTPN5 protein expression at 1 week after stress procedure. *p < 0.05. Error bars indicate SEM.
Figure 4.
Figure 4.
PTPN5 loss of function increases susceptibility to develop stress-related cognitive and morphological changes. A, Schematic representation of the experimental designs for examining the stress-induced impairment of long-term synaptic plasticity and the OLM in rats receiving bilateral intra-DH injections of sh-DsRed or sh-PTPN5 before stress treatment. B, Representative images showing the delivery of EGFP sh-PTPN5 in the CA1 region of the DH. Scale bar, 500 μm. C, Representative Western blots confirming stable silencing of PTPN5 expression by sh-PTPN5 (n = 4 in each group). D, Pie chart and bar graph showing the relative distribution of the OLM performance in rats by subtracting poststress values from prestress values at 1 week after stress procedure. The susceptibility was defined as index <80%. The naive group represents the individual rat receiving no treatment. E, Pie chart and bar graph showing the relative distribution of dendritic spine density in hippocampal CA1 pyramidal cells at 1 week after stress procedure. The number <45 per 50 μm was classified as susceptible. F, Summary of experiments showing the effect of stress on subsequent LTP induction in slices (prepared immediately after stress) from sh-DsRed- or sh-PTPN5-treated rats (n = 4 in each group). G, Summary of experiments showing the effect of stress on subsequent LTD induction in slices (prepared immediately after stress) from sh-DsRed- or sh-PTPN5-treated rats (n = 4 in each group). H, Representative immunoblots and corresponding densitometric analysis showing ERK1/2 phosphorylation in hippocampal CA1 region of sh-DsRed- or sh-PTPN5-treated rats immediately (S0) and 24 h (S24) after stress (n = 4). I, Summary of experiments showing the induction of LTP in slices from naive, sh-DsRed-treated, or sh-PTPN5-treated rats at 24 h after stress procedure (n = 4 in each group). J, Summary of experiments showing the induction of LTD in slices from naive, sh-DsRed-treated, or sh-PTPN5-treated rats at 24 h after stress procedure (n = 4 in each group). Each value in parentheses is the number of animals showing susceptibility relative to total number of animals examined. *p < 0.05. Error bars indicate SEM.
Figure 5.
Figure 5.
PTPN5 gain of function decreases susceptibility to develop stress-related cognitive and morphological changes. A, Schematic representation of the experimental designs for examining the stress-induced impairment of synaptic plasticity and the OLM in rats receiving bilateral intrahippocampal injections of LV-PTPN5 before stress treatment. B, Representative images showing the delivery of EGFP LV-PTPN5 in the CA1 region of the DH. Scale bar, 500 μm. C, Representative Western blots and PTPN5 phosphatase activity assay confirming stably overexpressing PTPN5 active variant by LV-PTPN5 (n = 5 in each group). D, Summary of experiments showing the induction of LTP in slices from naive, LV-EGFP-treated, or LV-PTPN5-treated rats at 1 h after stress procedure (n = 4 in each group). E, Summary of experiments showing the induction of LTD in slices from naive, LV-EGFP-treated, or LV-PTPN5-treated rats at 1 h after stress procedure (n = 4 in each group). F, Representative immunoblots and corresponding densitometric analysis showing ERK1/2 phosphorylation in hippocampal CA1 region of LV-EGFP- or LV-PTPN5-treated rats immediately (S0), 1 h (S1), or 24 h (S24) after stress (n = 4). G, Pie chart and bar graph showing the relative distribution of the OLM in rats by subtracting poststress values from prestress values at 1 week after stress procedure. The susceptibility was defined as index <80%. H, Pie chart and bar graph showing the relative distribution of dendritic spine density in hippocampal CA1 pyramidal cells at 1 week after stress procedure. The number <45 per 50 μm was classified as susceptible. Each value in parentheses is the number of animals showing susceptibility relative to total number of animals examined. *p < 0.05. Error bars indicate SEM.
Figure 6.
Figure 6.
The blockade of ERK1/2 downstream signaling pathway decreases susceptibility to develop stress-related cognitive and morphological changes. A, B, Representative immunoblots and corresponding densitometric analysis showing protein phosphorylation or expression levels in hippocampal CA1 region of sh-DsRed- or sh-PTPN5-treated rats at different time points after stress procedure (n = 5). *p < 0.05 compared with sh-DsRed group. C, Schematic representation of the experimental designs for examining the stress-induced impairment of the OLM in rats receiving bilateral intrahippocampal injections of sh-PTPN5 before stress and ERKI (5 mg/kg) treatment at 24 h after stress procedure. D, Representative immunoblots and corresponding densitometric analysis showing CaV1.2 protein expression in hippocampal CA1 region of sh-PTPN5-treated rats at 1 week after stress procedure with vehicle or ERKI treatment (n = 4 in each group). E, Pie chart and bar graph showing the relative distribution of the OLM in rats by subtracting poststress values from prestress values at 1 week after stress procedure with vehicle or ERKI treatment. The susceptibility was defined as index <80%. F, Pie chart and bar graph showing the relative distribution of dendritic spine density in hippocampal CA1 pyramidal cells at 1 week after stress procedure with vehicle or ERKI treatment. The number <45 per 50 μm was classified as susceptible. Each value in parentheses is the number of animals showing susceptibility relative to total number of animals examined. Error bars indicate SEM.
Figure 7.
Figure 7.
PTPN5 loss of function increases excitatory overload. A, Representative immunoblots and corresponding densitometric analysis showing CaV1.2 protein expression in hippocampal CA1 region of NS, US, or SUS rats at 1 week after stress procedure (n = 4 in each group). B, Correlation analysis of the discrimination index in the OLM and CaV1.2 protein expression in the DH at 1 week after stress procedure. C, Correlation analysis of the number of dendritic spines in hippocampal CA1 pyramidal cells and CaV1.2 protein expression in the DH at 1 week after stress procedure. D, E, Summary of experiments showing the relative rate of cell death using the DNA fragmentation assay (D) or the LDH release assay (E) in slices from sh-DsRed-treated or sh-PTPN5-treated rats after treatment with different glutamate concentrations (n = 5 in each group). LD50 represents the median lethal dose. F, G, Summary of experiments showing the relative rate of cell death using the DNA fragmentation assay (F) or the LDH release assay (G) in slices from sh-DsRed-treated or sh-PTPN5-treated rats after treatment with different Bay K8644 concentrations (n = 5 in each group). H, Schematic representation of the experimental designs for examining the stress-induced impairment of the OLM in rats receiving bilateral intra-DH injections of sh-PTPN5 before stress and nifedipine (2 mg · kg−1 · d−1) treatment at different time points after stress. I, Pie chart and bar graph showing the relative distribution of the OLM in rats by subtracting poststress values from prestress values at 1 week after stress procedure with nifedipine or saline treatment. The susceptibility was defined as index <80%. J, Pie chart and bar graph showing the relative distribution of dendritic spine density in hippocampal CA1 pyramidal cells at 1 week after stress procedure with nifedipine or saline treatment. The number <45 per 50 μm was classified as susceptible. Each value in parentheses is the number of animals showing susceptibility relative to total number of animals examined. *p < 0.05. Error bars indicate SEM.
Figure 8.
Figure 8.
CaV1.2 loss of function decreases stress susceptibility in sh-PTPN5-treated rats. A, Schematic representation of the experimental designs for examining the stress-induced impairment of the OLM in rats receiving bilateral intrahippocampal injections of sh-PTPN5 before stress and sh-Cav1.2 treatment at 24 h after stress procedure. B, Representative immunoblots and corresponding densitometric analysis showing Cav1.2 protein expression in hippocampal CA1 region of sh-PTPN5-treated rats at 1 week after stress procedure with sh-DsRed or sh-Cav1.2 treatment (n = 4 in each group). C, Pie chart and bar graph showing the relative distribution of the OLM in rats by subtracting poststress values from prestress values at 1 week after stress procedure with sh-DsRed or sh-Cav1.2 treatment. The susceptibility was defined as index <80%. D, Pie chart and bar graph showing the relative distribution of dendritic spine density in hippocampal CA1 pyramidal cells at 1 week after stress procedure with sh-DsRed or sh-Cav1.2 treatment. The number <45 per 50 μm was defined as susceptibility. *p < 0.05. Error bars indicate SEM.

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