Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance

Weitzdoerfer, Rachel; Hoeger, Harald; Engidawork, Ephrem; Engelmann, Mario; Singewald, Nicolas; Lübec, Gert; Lubec, Barbara

doi:10.1016/j.niox.2004.03.007

Cited by 104 publications

(53 citation statements)

References 60 publications

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“…Nitric oxide can dramatically modulate brain cGMP systems, suggesting that these systems may provide some of the primary targets for the products of nitric oxide synthases (NOS). Mnemonic and addictive functions can each be altered by changes in cGMP-dependent protein kinase and/or NOS [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

Uhl¹,

Liu²,

Drgon³

et al. 2007

BMC Genet

146

125

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Background: Classical genetic studies indicate that nicotine dependence is a substantially heritable complex disorder. Genetic vulnerabilities to nicotine dependence largely overlap with genetic vulnerabilities to dependence on other addictive substances. Successful abstinence from nicotine displays substantial heritable components as well. Some of the heritability for the ability to quit smoking appears to overlap with the genetics of nicotine dependence and some does not. We now report genome wide association studies of nicotine dependent individuals who were successful in abstaining from cigarette smoking, nicotine dependent individuals who were not successful in abstaining and ethnically-matched control subjects free from substantial lifetime use of any addictive substance.

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Section: Discussionmentioning

confidence: 99%

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

Uhl¹,

Liu²,

Drgon³

et al. 2007

BMC Genet

146

125

View full text Add to dashboard Cite

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“…Nowhere is this more important than in the central nervous system, where alterations in cAMP or cGMP concentrations can affect any and all aspects of brain function, including sensory processing, learning, and memory (Kandel, 2001;Prickaerts et al, 2002a). Support for specific actions of cGMP in controlling neurotransmission comes from studies of genetically modified mice lacking components of cGMP-generating pathways (i.e., NOS1, NO-GC1, and NO-GC2 knockout mice) and from pharmacological disruptions of cGMP pathways that result in impaired hippocampal synaptic plasticity or cognitive performance in hippocampal-mediated tasks (Weitzdoerfer et al, 2004;Hopper and Garthwaite, 2006;Taqatqeh et al, 2009). Consistent with the hypothesis that elevation of cGMP enhances hippocampal plasticity, learning, and memory, pharmacological studies of inhibitors of cGMP hydrolysis, including PDE9A inhibitors, have found that these compounds enhanced longterm potentiation (LTP) and performance in novel object recognition tasks in a time-sensitive fashion and in deficit settings that include tryptophan depletion and aging (Prickaerts et al, 2002a(Prickaerts et al, ,b, 2004Boess et al, 2004;Rutten et al, 2007;Menniti et al, 2008;van Donkelaar et al, 2008;van der Staay et al, 2008;Hutson et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase 9A Regulates Central cGMP and Modulates Responses to Cholinergic and Monoaminergic Perturbation In Vivo

Kleiman¹,

Chapin²,

Christoffersen³

et al. 2012

J Pharmacol Exp Ther

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Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a highaffinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

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“…Putative linkage between learning/memory and dementia NO application (Pitsikas et al 2005) or NO-sGC activation (Chien et al 2005) causes memory improvement, whereas NOS inhibition (Kopf et al 2001) or neuronal NOS knockout (Weitzdoerfer et al 2004) causes memory impairment. Thus it has generally been believed that NO enhances learning and memory.…”

mentioning

confidence: 99%

Nitric Oxide Activates Leak K⁺ Currents in the Presumed Cholinergic Neuron of Basal Forebrain

Kang¹,

Dempo²,

Ohashi³

et al. 2007

Journal of Neurophysiology

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T. Nitric oxide activates leak K ϩ currents in the presumed cholinergic neuron of basal forebrain. J Neurophysiol 98: [3397][3398][3399][3400][3401][3402][3403][3404][3405][3406][3407][3408][3409][3410] 2007. First published October 10, 2007; doi:10.1152/jn.00536.2007. Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K ϩ channels. Many neuromodulators closing leak K ϩ channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K ϩ channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromoguanosine-3Ј,5Ј-cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at -70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K ϩ equilibrium potential (E K ) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K ϩ current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 M Rp-8-bromo-␤-phenyl-1,N 2 -ethenoguanosine 3Ј,5Ј-cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than E K and close to the reversal potential of Na ϩ -K ϩ pump current. These observations strongly suggest that NO activates leak K ϩ channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na ϩ -K ϩ pump through ATP depletion.

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Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance

Cited by 104 publications

References 60 publications

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

Phosphodiesterase 9A Regulates Central cGMP and Modulates Responses to Cholinergic and Monoaminergic Perturbation In Vivo

Nitric Oxide Activates Leak K⁺ Currents in the Presumed Cholinergic Neuron of Basal Forebrain

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Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance

Cited by 104 publications

References 60 publications

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

Phosphodiesterase 9A Regulates Central cGMP and Modulates Responses to Cholinergic and Monoaminergic Perturbation In Vivo

Nitric Oxide Activates Leak K+ Currents in the Presumed Cholinergic Neuron of Basal Forebrain

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Nitric Oxide Activates Leak K⁺ Currents in the Presumed Cholinergic Neuron of Basal Forebrain