Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.

Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quino-line], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.Phosphodiesterase 10A (PDE10A) inhibition has generated much excitement as a potential novel mechanism for the treatment of the positive symptoms of schizophrenia (Menniti et al., 2007;Siuciak, 2008 ABBREVIATIONS: PDE10A, phosphodiesterase 10A; MP-10, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethy]-quinoline; TP-10, 2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline; MK-801, dizocilpine maleate; CREB, cAMP-response element-binding protein; pCREB, phospho-cAMP-response element-binding protein; DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass; pDARPP-32, phosphodopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass; PKA, protein kinase A; cGKII, cGMP-dependent kinase type II; D1, dopamine receptor subtype 1; D2, dopamine receptor subtype 2; GluR1, glutamate receptor subunit 1; pGluR1, phosphoglutamate receptor subunit 1; GluR2/3, glutamate receptor subunit 2/glutamate receptor subunit 3; pGluR2/3, phosphoglutamate receptor subunit 2/phosphoglutamate receptor subunit 3; NMDA, N-methyl-D-aspartate; NR2B, NMDA ...

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-D-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca 2ϩ assays (EC 50 ϭ 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 M) and competed for binding of3 H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) ϭ 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED ϭ 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED ϭ 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED ϭ 1 mg/kg i.p.) and reduced impulsivity in the fivechoice serial reaction time test (MED ϭ 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.The metabotropic glutamate receptor (mGlu) receptor family includes eight G-protein-coupled receptor (GPCR) subtypes classified on the basis of structural homology, Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.136580.ABBREVIATIONS: mGlu, metabotropic glutamate receptor; GPCR, G-protein-coupled receptor; PAM, positive allosteric modulator; CPPHA, 2, NMDA, MPEP,

Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A −/− knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a twoto threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatricdisease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate α-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (γ2) and γ8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.

The ␣7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of ␣7 nAChR. SEN12333 shows high affinity for the rat ␣7 receptor expressed in GH4C1 cells (K i ϭ 260 nM) and acts as full agonist in functional Ca 2ϩ flux studies (EC 50 ϭ 1.6 M). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC 50 ϭ 12 M). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at ␣3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the ␣7-selective antagonist methyllycaconitine, indicating that it is mediated by ␣7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel ␣7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of ␣7 agonists for treatment of neurodegenerative and cognitive disorders.The family of nicotinic acetylcholine receptors, which comprises 16 different subunits in human (␣1-7, ␣9 -10, ␤1-4, ␦, ε, and ␥) that can form many functional homo-and heteropentameric receptor ion channel combinations, contributes to cholinergic neurotransmission in the nervous system and at the neuromuscular junction. The ␣7 nicotinic acetylcholine receptors (nAChRs) are rapidly desensitizing ligand-gated ion channels that are abundantly expressed in the cerebral cortex and the hippocampus, a limbic structure intimately linked to attention processing and memory formation (Gotti et al., 2006). In the hippocampus, ␣7 nAChRs are present in interneurons and glutamatergic pyramidal neurons, in which they are localized presynaptically in nerve terminals and postsynaptically in dendritic spines and soma. In line with their localization, ␣7 nAChRs modulate neurotransmitter release and are responsible for direct fast excitatory neuroArticle, publication date, and citation information can be found at