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Mice lacking integrin β3 expression exhibit altered response to chronic stress.

Varney S, Polston KF, Jessen T, Carneiro AM - Neurobiol Stress (2015)

Bottom Line: We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test.Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain.Moreover, loss of integrin β3 expression modifies this correlation network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.

ABSTRACT

Recent studies indicate multiple roles for integrin αvβ3 in adult neurons, including response to pharmacological agents such as cocaine and selective serotonin reuptake inhibitors. In this study, we examined the role of the integrin β3 gene (Itgb3) in the response to environmental stimuli by subjecting Itgb3 (+/+) and Itgb3 (-/-) mice to unpredictable chronic mild stressors. We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test. In this test, chronic stress elicited significant decreases in stereotypic behavior and horizontal locomotor activity, including increases in anxiety behaviors. Mild chronic stress led to reductions in dopamine turnover in midbrains of Itgb3 (+/+), but not Itgb3 (-/-) mice, suggesting a disruption of stress-dependent regulation of DA homeostasis. Chronic stress elicited altered synaptic expression of syntaxin and synaptophysin in midbrains of Itgb3 (-/-) mice, when compared to Itgb3 (+/+). Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain. Moreover, loss of integrin β3 expression modifies this correlation network. Together, these findings demonstrate that Itgb3 (-/-) mice display a pattern of changes indicating disrupted regulation of midbrain synaptic systems involved in conferring resilience to mild stressors.

No MeSH data available.


Related in: MedlinePlus

Network diagram of proteins modulated by integrin αvβ3 expression levels during chronic stress response. We examined proteins that are either known to modulate stress vulnerability or response to antidepressants, or proteins that are regulated by integrin αvβ3 signaling. Of the 12 proteins examined, only 2 proteins have stress-induced reductions in expression in the context of Itgb3 loss-of-function (shown in black:syntaxin and synaptophysin), and 6 proteins have their synaptic expression correlated with midbrain synaptic αv (syntaxin, FAK, Src, ERK, PSD-95, NMDAR and GluR2). Expression correlations (indicated by a dashed line) are shown in wild-type mice (a), and in the context of integrin β3 loss of expression (b). Several of those proteins either form physical complexes or are phosphorylated by either FAK or Src, indicated by solid or double lines, respectively.
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Figure 3: Network diagram of proteins modulated by integrin αvβ3 expression levels during chronic stress response. We examined proteins that are either known to modulate stress vulnerability or response to antidepressants, or proteins that are regulated by integrin αvβ3 signaling. Of the 12 proteins examined, only 2 proteins have stress-induced reductions in expression in the context of Itgb3 loss-of-function (shown in black:syntaxin and synaptophysin), and 6 proteins have their synaptic expression correlated with midbrain synaptic αv (syntaxin, FAK, Src, ERK, PSD-95, NMDAR and GluR2). Expression correlations (indicated by a dashed line) are shown in wild-type mice (a), and in the context of integrin β3 loss of expression (b). Several of those proteins either form physical complexes or are phosphorylated by either FAK or Src, indicated by solid or double lines, respectively.

Mentions: Biochemical studies revealed correlation between midbrain synaptic expression levels of αv with signaling kinases, especially in the context of Itgb3-/- . The αv-containing receptors may participate in a molecular network modulating pre- and post-synaptic plasticity during the adaptive response to chronic stress (Fig. 3). In the absence of integrin β3 expression, αv correlates with synaptic expression of multiple proteins that modulate synaptic plasticity (GluR2, NMDAR and PSD-95), perhaps via compensatory expression of other integrin subunits. Of those, only GluR2 levels are correlated with synaptic integrin β1 levels (Pearson's r = 0.929, P = 0.003), indicating that other β subunits may also participate in this network. A possible interpretation of correlation results is that Itgb3 modifies a common factor influencing all proteins within this network. We also observed significant decreases in midbrain synaptic expression of syntaxin in Itgb3-/- mice, effects that were also correlated with total vertical activity time (Pearson's r = −0.923, P = 0.001), and synaptic levels of integrin β1 (Pearson's r = 0.871, P = 0.005). Thus, loss of integrin β3 expression may allow for the coordinated targeting of integrin αvβ1 and syantaxin to synapses. However, synaptoneurosomal preparation precludes the identification of specific neuronal subtypes in which these changes may be occurring, and our findings may arise from small changes in multiple systems, or in large alterations in specific neurotransmitter pathways. Future studies with conditional mutant lines should reveal the pathways that are directly influenced by Itgb3. Taken together, our data indicates that loss of integrin β3 expression significantly alters the coupling of integrins to monoamine metabolism and trafficking of presynaptic proteins to synapses, thus influencing the response to environmental stimuli.


Mice lacking integrin β3 expression exhibit altered response to chronic stress.

Varney S, Polston KF, Jessen T, Carneiro AM - Neurobiol Stress (2015)

Network diagram of proteins modulated by integrin αvβ3 expression levels during chronic stress response. We examined proteins that are either known to modulate stress vulnerability or response to antidepressants, or proteins that are regulated by integrin αvβ3 signaling. Of the 12 proteins examined, only 2 proteins have stress-induced reductions in expression in the context of Itgb3 loss-of-function (shown in black:syntaxin and synaptophysin), and 6 proteins have their synaptic expression correlated with midbrain synaptic αv (syntaxin, FAK, Src, ERK, PSD-95, NMDAR and GluR2). Expression correlations (indicated by a dashed line) are shown in wild-type mice (a), and in the context of integrin β3 loss of expression (b). Several of those proteins either form physical complexes or are phosphorylated by either FAK or Src, indicated by solid or double lines, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664197&req=5

Figure 3: Network diagram of proteins modulated by integrin αvβ3 expression levels during chronic stress response. We examined proteins that are either known to modulate stress vulnerability or response to antidepressants, or proteins that are regulated by integrin αvβ3 signaling. Of the 12 proteins examined, only 2 proteins have stress-induced reductions in expression in the context of Itgb3 loss-of-function (shown in black:syntaxin and synaptophysin), and 6 proteins have their synaptic expression correlated with midbrain synaptic αv (syntaxin, FAK, Src, ERK, PSD-95, NMDAR and GluR2). Expression correlations (indicated by a dashed line) are shown in wild-type mice (a), and in the context of integrin β3 loss of expression (b). Several of those proteins either form physical complexes or are phosphorylated by either FAK or Src, indicated by solid or double lines, respectively.
Mentions: Biochemical studies revealed correlation between midbrain synaptic expression levels of αv with signaling kinases, especially in the context of Itgb3-/- . The αv-containing receptors may participate in a molecular network modulating pre- and post-synaptic plasticity during the adaptive response to chronic stress (Fig. 3). In the absence of integrin β3 expression, αv correlates with synaptic expression of multiple proteins that modulate synaptic plasticity (GluR2, NMDAR and PSD-95), perhaps via compensatory expression of other integrin subunits. Of those, only GluR2 levels are correlated with synaptic integrin β1 levels (Pearson's r = 0.929, P = 0.003), indicating that other β subunits may also participate in this network. A possible interpretation of correlation results is that Itgb3 modifies a common factor influencing all proteins within this network. We also observed significant decreases in midbrain synaptic expression of syntaxin in Itgb3-/- mice, effects that were also correlated with total vertical activity time (Pearson's r = −0.923, P = 0.001), and synaptic levels of integrin β1 (Pearson's r = 0.871, P = 0.005). Thus, loss of integrin β3 expression may allow for the coordinated targeting of integrin αvβ1 and syantaxin to synapses. However, synaptoneurosomal preparation precludes the identification of specific neuronal subtypes in which these changes may be occurring, and our findings may arise from small changes in multiple systems, or in large alterations in specific neurotransmitter pathways. Future studies with conditional mutant lines should reveal the pathways that are directly influenced by Itgb3. Taken together, our data indicates that loss of integrin β3 expression significantly alters the coupling of integrins to monoamine metabolism and trafficking of presynaptic proteins to synapses, thus influencing the response to environmental stimuli.

Bottom Line: We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test.Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain.Moreover, loss of integrin β3 expression modifies this correlation network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.

ABSTRACT

Recent studies indicate multiple roles for integrin αvβ3 in adult neurons, including response to pharmacological agents such as cocaine and selective serotonin reuptake inhibitors. In this study, we examined the role of the integrin β3 gene (Itgb3) in the response to environmental stimuli by subjecting Itgb3 (+/+) and Itgb3 (-/-) mice to unpredictable chronic mild stressors. We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test. In this test, chronic stress elicited significant decreases in stereotypic behavior and horizontal locomotor activity, including increases in anxiety behaviors. Mild chronic stress led to reductions in dopamine turnover in midbrains of Itgb3 (+/+), but not Itgb3 (-/-) mice, suggesting a disruption of stress-dependent regulation of DA homeostasis. Chronic stress elicited altered synaptic expression of syntaxin and synaptophysin in midbrains of Itgb3 (-/-) mice, when compared to Itgb3 (+/+). Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain. Moreover, loss of integrin β3 expression modifies this correlation network. Together, these findings demonstrate that Itgb3 (-/-) mice display a pattern of changes indicating disrupted regulation of midbrain synaptic systems involved in conferring resilience to mild stressors.

No MeSH data available.


Related in: MedlinePlus