Impaired cognitive performance in neuronal nitric oxide synthase knockout mice is associated with hippocampal protein derangements

Kirchner, Lieselotte; Weitzdoerfer, Rachel; Hoeger, Harald; Url, Angelika; Schmidt, Peter; Engelmann, Mario; Villar, Santiago Rosell; Fountoulakis, Michael; Lübec, Gert; Lubec, Barbara

doi:10.1016/j.niox.2004.10.005

Cited by 54 publications

(32 citation statements)

References 38 publications

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“…This may suggest that neuroadaptations in the nNOS KO mice in the amygdalamore so than in the hippocampusresulted in NO-independent fear learning. Protein expression analysis of nNOS KO mice has revealed aberrant protein expression in the hippocampus (Kirchner et al 2004) that may underlie the deficits in contextual fear learning observed in the present study, as well as other cognitive deficits ).…”

Section: No and Fear Conditioningmentioning

confidence: 55%

Impairments in fear conditioning in mice lacking the nNOS gene

et al. 2009

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The fear conditioning paradigm is used to investigate the roles of various genes, neurotransmitters, and substrates in the formation of fear learning related to contextual and auditory cues. In the brain, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) functions as a retrograde neuronal messenger that facilitates synaptic plasticity, including the late phase of long-term potentiation (LTP) and formation of long-term memory (LTM). Evidence has implicated NO signaling in synaptic plasticity and LTM formation following fear conditioning, yet little is known about the role of the nNOS gene in fear learning. Using knockout (KO) mice with targeted mutation of the nNOS gene and their wild-type (WT) counterparts, the role of NO signaling in fear conditioning was investigated. Plasma levels of the stress hormone corticosterone were measured to determine the relationship between physiological and behavioral response to fear conditioning. Contextual fear learning was severely impaired in male and female nNOS KO mice compared with WT counterparts; cued fear learning was slightly impaired in nNOS KO mice. Sex-dependent differences in both contextual and cued fear learning were not observed in either genotype. Deficits in contextual fear learning in nNOS KO mice were partially overcome by multiple trainings. A relationship between increase in plasma corticosterone levels following footshock administration and the magnitude of contextual, but not cued freezing was also observed. Results suggest that the nNOS gene contributes more to optimal contextual fear learning than to cued fear learning, and therefore, inhibition of the nNOS enzyme may ameliorate context-dependent fear response.Anxiety disorders, such as post-traumatic stress disorder (PTSD), constitute the most prevalent mental illnesses in the United States, costing nearly one-third of the country's total health bill (Greenberg et al. 1999). The treatment of these disorders requires overcoming complications such as reluctance to seek mental health treatment and an extremely high comorbidity rate with other affective disorders, reaching 80% (Brady 1997;Solomon and Davidson 1997). Emerging evidence suggests that dysfunctions underlying acquired anxiety and PTSD include an abnormal reaction to stress, which is mediated by specific neurochemical and neuroanatomical substrates (Yehuda and McFarlane 1995;Adamec 1997). Pharmacotherapies that target neuronal signaling molecules, such as nitric oxide (NO), may play a role in the treatment of these disorders.In the brain, N-methyl-D-aspartate receptor (NMDAR) activation and calcium influx into the cell activates the neuronal nitric oxide synthase (nNOS) enzyme to produce NO, which has the role of retrograde messenger (Snyder 1992). NO is involved in memory formation and synaptic plastic events such as late-phase long-term potentiation (LTP) (Lu et al. 1999;Arancio et al. 2001;Puzzo et al. 2006). Behavioral evidence in invertebrates (Lewin and Walters 1999;Muller 2000;Kemenes et al. 2002;Matsumoto et al. 2006) ...

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Section: No and Fear Conditioningmentioning

confidence: 55%

Impairments in fear conditioning in mice lacking the nNOS gene

et al. 2009

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“…Fourth, a nitric oxide-guanylate cyclase activator enhances learning behavior and antagonizes scopolamine-induced learning impairment (Chien et al 2005). Fifth, mice, lacking the gene for n-NOS but not for e-NOS, show impaired cognitive performance (Dere et al 2001;Kirchner et al 2004;Weitzdoerfer et al 2004). Although the polyamine's effects on memory seem to be linked to the NMDAr, up to now, no study has addressed if these effects involve NO production.…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide is involved in the memory facilitation induced by spermidine in rats

et al. 2006

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“…Aberrant levels of elongation factor Tu were observed in the above-mentioned SOD1 transgenic mouse, and aberrant hippocampal protein levels of heterogeneous nuclear ribonucleoprotein H were observed in memory-deficient nNOS knock-out mice (Kirchner et al, 2004). Differences between splicing in the mouse strains herein are supported by differential expression of heterogeneous nuclear ribonucleoprotein D-like.…”

Section: Discussionmentioning

confidence: 64%

Differences in hippocampal protein levels between C57Bl/6J, PWD/PhJ, and Apodemus sylvaticus are paralleled by differences in spatial memory

et al. 2011

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There is a significant strain-dependent performance in the Morris water maze (MWM), a paradigm for the evaluation of spatial memory. In contrast, information on molecular differences that may be responsible for differences in spatial memory performance is limited. The aim of the study was therefore to investigate differences in hippocampal protein levels in three groups with different performance in the MWM. C57BL/6J (inbred laboratory strain), PWD/PhJ (inbred strain derived from wild animals of Mus musculus), and Apodemus sylvaticus (AS, genus Apodemus) mice were used for the experiments. Proteins from hippocampi, obtained from a behavioral study on these animals, were extracted and run on two-dimensional gel electrophoresis. Proteins spots were quantified, and spots with significantly different levels were identified by mass spectrometry using an ion trap. A series of 49 proteins from different pathways and cascades (signaling, neuronal network, protein synthesis, secretion and degradation, and antioxidant system; intermediary, fat, and carbohydrate metabolism) were significantly different among hippocampi at the stringent statistical level of P ≤ 0.001. These findings are paralleled by differences in the spatial navigation abilities between the strains within the species Mus musculus (C57BL/6 vs. PWD/PhJ) and between the genera Mus and Apodemus. As shown previously, AS learned the task in the MWM and showed good memory retention when tested at the probe trial (day 12), whereas C57BL/6J learned the task, but failed at the probe trial at day 12 as well as PWD/PhJ that failed to learn the task and failed at the probe trial at day 12. A list of above-mentioned proteins were different between PWD/PhJ with bad and AS with good memory retention and may therefore be related to performance in the MWM and thus to spatial memory formation. The experimental approach, however, does not allow discriminating between differences in protein levels a priori and different protein levels induced by the MWM testing. © 2010 Wiley-Liss, Inc.

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Impaired cognitive performance in neuronal nitric oxide synthase knockout mice is associated with hippocampal protein derangements

Cited by 54 publications

References 38 publications

Impairments in fear conditioning in mice lacking the nNOS gene

Impairments in fear conditioning in mice lacking the nNOS gene

Nitric oxide is involved in the memory facilitation induced by spermidine in rats

Differences in hippocampal protein levels between C57Bl/6J, PWD/PhJ, and Apodemus sylvaticus are paralleled by differences in spatial memory

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