Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice.

Aims: Neurogranin (NRGN) is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. Recent studies suggest that NRGN is involved in neuropsychiatric disorders, including schizophrenia, ADHD, and Alzheimer's disease. Previous behavioral studies of Nrgn knockout (Nrgn KO) mice identified hyperactivity, deficits in spatial learning, impaired sociability, and decreased prepulse inhibition, which suggest that these mice recapitulate some symptoms of neuropsychiatric disorders.

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders.

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies.

Calcium-Sensitive Translocation of Calmodulin and Neurogranin between Soma and Dendrites of Mouse Hippocampal CA1 Neurons.

Calmodulin (CaM) and neurogranin (Ng) are two abundant neuronal proteins whose interactions are implicated in the regulation of synaptic responses and plasticity. We employed the "low-calcium" model of epilepsy in hippocampal slices to investigate the mobilization of these two proteins in CA1 pyramidal neurons. Perfusion of mouse hippocampal slices with Ca(2+)-free artificial CSF (ACSF) caused a suppression of synaptic transmission and generation of epileptic activity; these responses could be reversed by normal Ca(2+)-containing ACSF.

Ischemia-elicited oxidative modulation of Ca2+/calmodulin-dependent protein kinase II.

Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) plays a critical role in neuronal signal transduction and synaptic plasticity. Here, we showed that this kinase was very susceptible to oxidative modulation. Treatment of mouse brain synaptosomes with H2O2, diamide, and sodium nitroprusside caused aggregation of CaMKII through formation of disulfide and non-disulfide linkages, and partial inhibition of the kinase activity.

Long-term enrichment enhances the cognitive behavior of the aging neurogranin null mice without affecting their hippocampal LTP.

Neurogranin (Ng), a PKC substrate, is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng caused severe deficits in spatial learning and LTP in the hippocampal CA1 region of mice. These Ng-/- mice also exhibit deficits in the amplification of their hippocampal signaling pathways critical for learning and memory.

Modification of protein by disulfide S-monoxide and disulfide S-dioxide: distinctive effects on PKC.

Disulfide S-monoxide (DSMO) and disulfide S-dioxide (DSDO) have been proposed as proximal mediators for the oxidant-mediated modification of proteins. These disulfide S-oxides (DSOs) derived from glutathione (GSH) and captopril (CPSH) were synthesized by iron- or methyltrioxorhenium (VII)-catalyzed oxidation of the thiols with H2O2. Treatment of mouse hippocampal extracts with [35S]GS-DSOs revealed that a large number of proteins were susceptible to thionylation; however, only a limited number of the them were detectable by the commonly used antibody against GS-associated proteins.

Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice.

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region.

Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling.

In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng+/+, 160-370 and Ng+/-, approximately 70-230 pmol/mg); the level in Ng+/+ mice is one of the highest among all neuronal CaM-binding proteins. Among Ng+/- mice, but less apparent in Ng+/+, a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze.

Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+- and Ca2+/calmodulin-dependent neuronal signaling in the hippocampus.

Neurogranin/RC3 (Ng) is a postsynaptic protein kinase C (PKC) substrate and calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by Ca2+, phosphorylation and oxidation. Ng has been implicated in the modulation of postsynaptic signal transduction pathways and synaptic plasticity. Previously, we showed a severe deficit of spatial memory in Ng knockout (KO) mice.

Glutathionylation of proteins by glutathione disulfide S-oxide.

Aqueous solution of S-nitrosoglutathione (GSNO) underwent spontaneous chemical transformation that generated several glutathione derivatives including glutathione sulfonic acid (GSO3H), glutathione disulfide S-oxide (GS(O)SG), glutathione disulfide S-dioxide, and glutathione disulfide. Surprisingly, GS(O)SG (also called glutathione thiosulfinate), which was not identified as a metabolite of GSNO previously, was one of the major products derived from GSNO. This compound was very reactive toward any thiol and the reaction product was a mixed disulfide.

Attenuation of protein kinase C and cAMP-dependent protein kinase signal transduction in the neurogranin knockout mouse.

Neurogranin (Ng) is a brain-specific, postsynaptically located protein kinase C (PKC) substrate, highly expressed in the cortex, hippocampus, striatum, and amygdala. This protein is a Ca(2+)-sensitive calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by phosphorylation and oxidation. To investigate the role of Ng in neural function, a strain of Ng knockout mouse (KO) was generated.