Altered emotional behaviors in the diabetes mellitus OLETF type 1 congenic rat.

GPR10 is a G-protein-coupled receptor expressed in thalamic and hypothalamic brain regions, including the reticular thalamic nucleus (RTN) and periventricular nucleus (Pev), and the endogenous ligand for this receptor, prolactin-releasing peptide (PrRP), has demonstrated regulatory effects on the stress response. We produced a congenic rat by introducing the Dmo1 allele from the OLETF rat which encodes the amino acid sequences of GPR10 with a truncated NH2-terminus, into the Brown-Norway background. Using receptor autoradiography, we determined a lack of specific [125I]PrRP binding in the RTN and Pev of these mutant rats compared to the control rats. Furthermore, intracerebroventricular injection of PrRP did not induce a significant increase of c-fos-like immunoreactivity in the paraventricular nucleus of the mutant rats compared to the control rats. The mutant rats also displayed a less anxious-like phenotype in three behavioral-based models of anxiety-like behavior (open field, elevated plus maze and defensive withdrawal test). These data show the mutant congenic rat, of which GPR10 neither binds nor responds to PrRP, expresses less anxious-like phenotypes. On the basis of these observations, the GPR10 might be a novel target for the developing new drugs against anxiety and/or other stress-related diseases.

Reduction of NR1 and phosphorylated Ca2+/calmodulin-dependent protein kinase II levels in Alzheimer's disease.

Ca2+ influx through the N-methyl-D-aspartate-type glutamate receptor leads to activation and postsynaptic accumulation of Ca2+/calmodulin-dependent protein kinase II. NR1 and NR2B subunits of N-methyl-D-aspartate receptor serve as high-affinity Ca2+/calmodulin-dependent protein kinase II docking sites in dendritic spines on autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. By comparative Western blot analysis, we show a reduction of NR1 and phosphorylated Ca2+/calmodulin-dependent protein kinase II levels in the frontal cortex and hippocampus of Alzheimer's disease brains. We also found a significant correlation between phosphorylated Ca2+/calmodulin-dependent protein kinase II and NR1 levels. Our study extends the view that N-methyl-D-aspartate receptor deficiency underlies memory impairment in Alzheimer's disease, and that this process likely involves insufficient activation of Ca2+/calmodulin-dependent protein kinase II.

Enhanced long-term potentiation in vivo in dentate gyrus of NELL2-deficient mice.

NELL2 is a neuron-specific thrombospondin-1-like extracellular protein containing six epidermal growth factor-like domains and is highly expressed in the hippocampus. We have previously shown that NELL2 promotes survival of neurons through mitogen-activated protein kinases. To clarify the function of NELL2 in vivo, we have generated a novel strain of mice with a targeted mutation in the NELL2 gene and assessed long-term potentiation (LTP) in vivo in the dentate gyrus of NELL2-deficient mice using extracellular recording techniques. Production of LTP at perforant path-granule cell synapses was significantly larger in NELL2-deficient mice than in wild-type controls. Thus, we propose that NELL2 plays an important role as a novel suppressor in LTP in vivo in the mouse dentate gyrus.

The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release.

Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S) and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of prolactin release was less than that of DA. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded residual cAMP levels equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L) receptors expressed in GH4C1 cells. These data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with minimal potential for adverse events including no significant increase of serum prolactin levels in clinical studies.

A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases.

NELL2 is a neuron-specific thrombospondin-1-like extracellular protein containing six epidermal growth factor-like domains. NELL2 is highly expressed in the hippocampus and cerebral cortex. Although the involvement of NELL2 in neural functions has been inferred from its expression and biochemical profiles, biological roles of NELL2 remain uncertain. We evaluated the survival effect of NELL2 using primary cultured neurons from fetal rat brain following treatment with a recombinant NELL2 protein. NELL2 increased survival of neurons from the hippocampus and cerebral cortex. We further examined the protective effect of NELL2 from oxygen-glucose deprivation- and beta-amyloid-induced neuronal death, and found that NELL2 did not protect neurons from these insults. To understand signaling properties underlying the survival effect, we studied activation of mitogen-activated protein kinases (MAPKs) by NELL2. Treatment of primary cultured cells from the hippocampus with NELL2 enhanced phosphorylation of c-jun N-terminal kinase (JNK), whereas phosphorylation of extracellular signal-regulated kinase (ERK) was decreased by NELL2 treatment. NELL2-enhanced survival of hippocampal neurons was completely blocked by SP600125, an anthrapyrazolone inhibitor of JNK, while treatment of MEK (MAPK/ERK kinase) inhibitors per se enhanced survival of neurons similar to NELL2 treatment. These results suggest that NELL2 promotes survival of neurons by modulating MAPK activities.