PMC:3649690 / 21039-24500 JSONTXT

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Potential Role for PSA-NCAM in Antidepressant Efficacy\nThe expression of PSA-NCAM within the adult nervous system is essential in multiple facets of neural plasticity, including neurogenesis, synaptic plasticity, and neurite outgrowth [10, 30, 31, 97, 98]. Importantly, PSA-NCAM functions across all aspects of hippocampal neurogenesis (proliferation, migration, differentiation, and survival), therefore changes in the polysialylation of newly generated neurons alter neurogenesis as a whole [99–104] (see Table 2). For instance, chronic mild stress reduces the expression of both the core NCAM protein [65] and the addition of the PSA moiety [11, 105–108] in the hippocampus; however these changes are dependent on the type of stressor [109] (see Table 3). Alterations in PSA-NCAM expression following stress are also seen in other regions associated with depression including the amygdala and prefrontal cortex [110–113]. Similarly, PSA-NCAM expression is reduced in amygdala of patients with major depressive disorder [2, 114]; however no change is seen in the PFC [115]. Conversely, chronic antidepressant treatment modulates PSA-NCAM expression throughout the limbic system in animal models of depression. [11, 116–119]. Moreover, antidepressant treatment reduces PSA-NCAM expression in the dorsal raphe nucleus [116], implicating PSA-NCAM in antidepressant-induced plasticity related to serotonergic neurotransmission. Taken together these findings suggest PSA-NCAM may play a fundamental role in mediating broad effects of antidepressant treatment across multiple forms of neural plasticity.\nPrevious studies have shown PSA-NCAM is essential in the activity-dependent induction of hippocampal LTP and LTD [35], where the polysialylation of NCAM is positively correlated with neural activity of glutamatergic neurons [120, 121]. Moreover, inhibiting the polysialylation of NCAM reduces the rate of dendritic spine formation and decreases the stability of these spines [122]. Interestingly PSA-NCAM is also directly related to monoaminergic neurotransmission, as PSA-NCAM expression is directly modulated by the 5-HT1A receptor [123]. Moreover, serotonergic innervation plays a role in regulating the expression of PSA-NCAM in the hippocampus [124]. Given the interaction of serotonergic neurotransmission with PSA-NCAM and its putative role in regulating synaptic plasticity, it is possible that PSA-NCAM may mediate some of the effects of antidepressant treatment on monoaminergic tone. \nThe ability of PSA-NCAM to directly alter hippocampal neurogenesis is evidenced by the selective removal of the PSA moiety from NCAM with the bacteriophage enzyme EndoN. Application of EndoN disrupts normal migration of newly produced cells and alters differentiation of these new cells by shifting them toward a neuronal phenotype [10]. Selective cleavage of PSA also produces enhanced dendritic arborization, aberrant mossy fiber sprouting, produces ectopic synaptic bouton formation, and increases cell death within the hippocampus [97, 98]. \nGiven the role of PSA-NCAM in mediating multiple aspects of neural plasticity it appears to function at the confluence of the prevailing theories of depression: monoaminergic, neurotrophic, and neurogenic, thus making it an interesting target for future study. Further research is necessary to elucidate the role of PSA-NCAM and similar proteins, in the etiology of depression and efficacy of antidepressant drugs.\n"}

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Potential Role for PSA-NCAM in Antidepressant Efficacy\nThe expression of PSA-NCAM within the adult nervous system is essential in multiple facets of neural plasticity, including neurogenesis, synaptic plasticity, and neurite outgrowth [10, 30, 31, 97, 98]. Importantly, PSA-NCAM functions across all aspects of hippocampal neurogenesis (proliferation, migration, differentiation, and survival), therefore changes in the polysialylation of newly generated neurons alter neurogenesis as a whole [99–104] (see Table 2). For instance, chronic mild stress reduces the expression of both the core NCAM protein [65] and the addition of the PSA moiety [11, 105–108] in the hippocampus; however these changes are dependent on the type of stressor [109] (see Table 3). Alterations in PSA-NCAM expression following stress are also seen in other regions associated with depression including the amygdala and prefrontal cortex [110–113]. Similarly, PSA-NCAM expression is reduced in amygdala of patients with major depressive disorder [2, 114]; however no change is seen in the PFC [115]. Conversely, chronic antidepressant treatment modulates PSA-NCAM expression throughout the limbic system in animal models of depression. [11, 116–119]. Moreover, antidepressant treatment reduces PSA-NCAM expression in the dorsal raphe nucleus [116], implicating PSA-NCAM in antidepressant-induced plasticity related to serotonergic neurotransmission. Taken together these findings suggest PSA-NCAM may play a fundamental role in mediating broad effects of antidepressant treatment across multiple forms of neural plasticity.\nPrevious studies have shown PSA-NCAM is essential in the activity-dependent induction of hippocampal LTP and LTD [35], where the polysialylation of NCAM is positively correlated with neural activity of glutamatergic neurons [120, 121]. Moreover, inhibiting the polysialylation of NCAM reduces the rate of dendritic spine formation and decreases the stability of these spines [122]. Interestingly PSA-NCAM is also directly related to monoaminergic neurotransmission, as PSA-NCAM expression is directly modulated by the 5-HT1A receptor [123]. Moreover, serotonergic innervation plays a role in regulating the expression of PSA-NCAM in the hippocampus [124]. Given the interaction of serotonergic neurotransmission with PSA-NCAM and its putative role in regulating synaptic plasticity, it is possible that PSA-NCAM may mediate some of the effects of antidepressant treatment on monoaminergic tone. \nThe ability of PSA-NCAM to directly alter hippocampal neurogenesis is evidenced by the selective removal of the PSA moiety from NCAM with the bacteriophage enzyme EndoN. Application of EndoN disrupts normal migration of newly produced cells and alters differentiation of these new cells by shifting them toward a neuronal phenotype [10]. Selective cleavage of PSA also produces enhanced dendritic arborization, aberrant mossy fiber sprouting, produces ectopic synaptic bouton formation, and increases cell death within the hippocampus [97, 98]. \nGiven the role of PSA-NCAM in mediating multiple aspects of neural plasticity it appears to function at the confluence of the prevailing theories of depression: monoaminergic, neurotrophic, and neurogenic, thus making it an interesting target for future study. Further research is necessary to elucidate the role of PSA-NCAM and similar proteins, in the etiology of depression and efficacy of antidepressant drugs.\n"}