Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin

Madani, Rime; Kozlov, Serguei; Akhmedov, Alexander; Cinelli, Paolo; Kinter, Jochen; Lipp, Hans‐Peter; Sonderegger, P.; Wolfer, David P

doi:10.1016/s1044-7431(03)00077-0

Cited by 131 publications

(131 citation statements)

References 83 publications

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“…Locomotion and novelty-induced behavior have previously been assessed in neuroserpin-deficient mice (Madani et al 2003). Similarly to us, Madani and colleagues did not detect any difference between genotypes in the open-field paradigm.…”

Section: Discussionsupporting

confidence: 65%

“…Interestingly, rats injected with recombinant adenovirus expressing neuroserpin in the dorsal hippocampus were subjected to the same behavioral tests (Tsang et al 2014), but no alterations were detected, suggesting that the absence of neuroserpin, but not its overexpression, alters hippocampusdependent cognitive functions. The situation is different for the regulation of exploratory behavior and anxiety, because transgenic mice overexpressing neuroserpin in neurons under the control of the Thy1.2 promoter show similar behavioral abnormalities as do mice deficient in neuroserpin (Madani et al 2003). In addition, we observed deficits in social behavior toward an unfamiliar male mouse in neuroserpin-deficient mice.…”

Section: Discussionmentioning

confidence: 73%

“…Given the high expression of neuroserpin in the hippocampus, a brain region involved in cognition, dysregulated levels of neuroserpin reported in patients suffering neuropsychiatric disorders (Hakak et al 2001;Vawter et al 2004;Brennand et al 2011;Wen et al 2014), conditions characterized by altered synaptic function (Penzes et al 2011), and the absence of reports investigating social and cognitive function in neuroserpindeficient mice, we extended the previously reported behavioral study (Madani et al 2003) and assessed the role of neuroserpin in cognition and mental disorders by applying multiple testing paradigms to neuroserpin-deficient mice. We found impairments in spatial learning and memory in the water maze test and in associative learning in the contextual fear conditioning test.…”

Section: Discussionmentioning

confidence: 99%

“…Generation of neuroserpin-deficient mice (Ns−/−) has been previously described (Madani et al 2003). The strain was established on a mixed 129SvEv/C57BL/6 background and backcrossed into C57BL/6J for more than 10 generations.…”

Section: Animalsmentioning

confidence: 99%

“…Removal of Lynx1, a negative regulator of adult plasticity, leads to experience-dependent elevation of tPA and increased plasticity, a process blocked by administration of neuroserpin (Bukhari et al 2015). In addition to this direct evidence linking neuroserpin to synaptic function, translational data from schizophrenic patients, a disorder characterized by improper synaptic function, showed dysregulation of neuroserpin (Hakak et al 2001;Vawter et al 2004;Brennand et al 2011;Wen et al 2014), and mice with dysregulated expression of neuroserpin show selective reduction of locomotor activity in novel environments, anxiety-like response on the O-maze, and neophobic response to novel objects (Madani et al 2003). In this study, we demonstrate the essential role of neuroserpin in maintaining functional synapses in vivo.…”

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confidence: 94%

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The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

et al. 2017

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The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 94%

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The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

et al. 2017

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Similar reliability and equivalent performance of female and male mice in the open field and water‐maze place navigation task

Fritz

Amrein

Wolfer

2017

American J of Med Genetics Pt C

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Although most nervous system diseases affect women and men differentially, most behavioral studies using mouse models do not include subjects of both sexes. Many researchers worry that data of female mice may be unreliable due to the estrous cycle. Here, we retrospectively evaluated sex effects on coefficient of variation (CV) in 5,311 mice which had performed the same place navigation protocol in the water‐maze and in 4,554 mice tested in the same open field arena. Confidence intervals for Cohen's d as measure of effect size were computed and tested for equivalence with 0.2 as equivalence margin. Despite the large sample size, only few behavioral parameters showed a significant sex effect on CV. Confidence intervals of effect size indicated that CV was either equivalent or showed a small sex difference at most, accounting for less than 2% of total group to group variation of CV. While female mice were potentially slightly more variable in water‐maze acquisition and in the open field, males tended to perform less reliably in the water‐maze probe trial. In addition to evaluating variability, we also directly compared mean performance of female and male mice and found them to be equivalent in both water‐maze place navigation and open field exploration. Our data confirm and extend other large scale studies in demonstrating that including female mice in experiments does not cause a relevant increase of data variability. Our results make a strong case for including mice of both sexes whenever open field or water‐maze are used in preclinical research.

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Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress‐induced cognitive impairments

2010

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In rodents, chronic stress induces long-lasting structural and functional alterations in the hippocampus, as well as learning and memory impairments. The neural cell adhesion molecule (NCAM) was previously hypothesized to be a key molecule in mediating the effects of stress due to its role in neuronal remodeling and since chronic stress diminishes hippocampal NCAM expression in rats. However, since most of the evidence for these effects is correlative or circumstantial, we tested the performance of conditional NCAM-deficient mice in the water maze task to obtain causal evidence for the role of NCAM. We first validated that exposure to chronic unpredictable stress decreased hippocampal NCAM expression in C57BL/6 wild-type mice, inducing deficits in reversal learning and mild deficits in spatial learning. Similar deficits in water maze performance were found in conditional NCAM-deficient mice that could not be attributed to increased anxiety or enhanced corticosterone responses. Importantly, the performance of both the conditional NCAM-deficient mice and chronically stressed wild-type mice in the water maze was improved by post-training injection of the NCAM mimetic peptide, FGLs. Thus, these findings support the functional involvement of NCAM in chronic stress-induced alterations and highlight this molecule as a potential target to treat stress-related cognitive disturbances.

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Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin

Cited by 131 publications

References 83 publications

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

Similar reliability and equivalent performance of female and male mice in the open field and water‐maze place navigation task

Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress‐induced cognitive impairments

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