Prediction of Efficacy of Vabicaserin, a 5-HT2C Agonist, for the Treatment of Schizophrenia Using a Quantitative Systems Pharmacology Model.

A quantitative systems pharmacology model that combines in vitro/preclinical neurophysiology data, human imaging data, and patient disease information was used to blindly predict steady-state clinical efficacy of vabicaserin, a 5-HT2C full agonist, in monotherapy and, subsequently, to assess adjunctive therapy in schizophrenia. The model predicted a concentration-dependent improvement of positive and negative syndrome scales (PANSS) in schizophrenia monotherapy with vabicaserin. At the exposures of 100 and 200 mg b.i.d., the predicted improvements on PANSS in virtual patient trials were 5.12 (2.20, 8.56) and 6.37 (2.27, 10.40) (mean (95% confidence interval)), respectively, which are comparable to the observed phase IIa results. At the current clinical exposure limit of vabicaserin, the model predicted an ~9-point PANSS improvement in monotherapy, and <4-point PANSS improvement adjunctive with various antipsychotics, suggesting limited clinical benefit of vabicaserin in schizophrenia treatment. In conclusion, the updated quantitative systems pharmacology model of PANSS informed the clinical development decision of vabicaserin in schizophrenia.

Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation.

Local translation of proteins in distal dendrites is thought to support synaptic structural plasticity. We have previously shown that metabotropic glutamate receptor (mGluR1) stimulation initiates a phosphorylation cascade, triggering rapid association of some mRNAs with translation machinery near synapses, and leading to protein synthesis. To determine the identity of these mRNAs, a cDNA library produced from distal nerve processes was used to screen synaptic polyribosome-associated mRNA. We identified mRNA for the fragile X mental retardation protein (FMRP) in these processes by use of synaptic subcellular fractions, termed synaptoneurosomes. We found that this mRNA associates with translational complexes in synaptoneurosomes within 1-2 min after mGluR1 stimulation of this preparation, and we observed increased expression of FMRP after mGluR1 stimulation. In addition, we found that FMRP is associated with polyribosomal complexes in these fractions. In vivo, we observed FMRP immunoreactivity in spines, dendrites, and somata of the developing rat brain, but not in nuclei or axons. We suggest that rapid production of FMRP near synapses in response to activation may be important for normal maturation of synaptic connections.

Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits.

Fragile X syndrome arises from blocked expression of the fragile X mental retardation protein (FMRP). Golgi-impregnated mature cerebral cortex from fragile X patients exhibits long, thin, tortuous postsynaptic spines resembling spines observed during normal early neocortical development. Here we describe dendritic spines in Golgi-impregnated cerebral cortex of transgenic fragile X gene (Fmr1) knockout mice that lack expression of the protein. Dendritic spines on apical dendrites of layer V pyramidal cells in occipital cortex of fragile X knockout mice were longer than those in wild-type mice and were often thin and tortuous, paralleling the human syndrome and suggesting that FMRP expression is required for normal spine morphological development. Moreover, spine density along the apical dendrite was greater in the knockout mice, which may reflect impaired developmental organizational processes of synapse stabilization and elimination or pruning.

Increased density of multiple-head dendritic spines on medium-sized spiny neurons of the striatum in rats reared in a complex environment.

It has generally been assumed that new synapses added to various brain regions in response to experience are equivalent to those already in existence. Theorists have recently posited that synaptic configurations involving multiple associated contacts may facilitate plastic change. The number of multiple-headed dendritic spines on medium-sized spiny neurons in the rat dorsolateral corpus striatum was determined following rearing in environments differing in complexity. Postweaning rats were either housed as a group in a toy- and object-filled environment or housed individually in standard laboratory cages for 30 days. Dendritic segments of Golgi-Cox impregnated Type I spiny neurons of the complex environment housed rats had approximately 60% more multiple-head spines than those of the individually caged animals. Multiple-head spines may reflect parallel synaptic contacts that modify relative strengths of existing connections or connections with a novel presynaptic terminal that alter the neuron's pattern of connections.

Synaptogenesis and Fos expression in the motor cortex of the adult rat after motor skill learning.

Recent work has suggested that changes in synapse number as well as changes in the expression of the Fos protein may occur within the motor cortex in association with motor learning. The number of synapses per neuron and the percentage of Fos-positive neurons within layer II/III of the rat motor cortex was measured after training on a complex motor learning task. Adult female rats were allocated randomly to either an acrobatic condition (AC), a motor control condition (MC), or an inactive control condition (IC). AC animals were trained to traverse a complex series of obstacles, and each AC animal was pair matched with an MC animal that traversed an obstacle-free runway. IC animals received no motor training. Animals from each condition were killed at various points during training, and unbiased stereological techniques were used to estimate the number of synapses per neuron and the percentage of Fos-positive cells within layer II/III of the motor cortex. AC animals exhibited an overall increase in the number of synapses per neuron in comparison to MC and IC animals at later stages of training. AC animals also had a significantly higher overall percentage of Fos-positive cells in comparison to both controls, with a trend for the increase to be greater during the acquisition versus the maintenance phase. These data suggest that Fos may be involved in the biochemical processes underlying skill acquisition and that motor learning, as opposed to motor activity, leads to increases in synapse number in the motor cortex.

Expression of DMAP-45R in the rat visual cortex is modulated by visual experience.

Effects of visual experience upon expression of a developmentally regulated microtubule-associated protein (MAP) were studied in the visual cortex of monocularly deprived rats. The antibody Drosophila MAP-45 (DMAP-45) recognizes proteins in the developing ventral nerve cord of Drosophila and in rat brain. Monocular deprivation from day 12, before eye opening, to day 80 reduced the number of DMAP-45 immunoreactive layer V pyramidal cell apical dendrites in the monocular segment (Oc1M) of the visual cortex contralateral to the deprived eye. No significant visual deprivation effects were seen in the binocular segment (Oc1B). Immunoreactivity was restored to control levels in Oc1M of rats in which the monocular sutures were removed at day 75, subsequently allowing 5 days of exposure to light. These results indicate potential involvement of this MAP in experience-dependent structural plasticity.

Differential rearing alters spine density on medium-sized spiny neurons in the rat corpus striatum: evidence for association of morphological plasticity with early response gene expression.

Morphological plasticity of medium-sized spiny neurons of the striatum was examined in Long-Evans hooded rats reared in complex or individual cage environments. Rat pups, aged 28-32 days, were housed either individually in standard laboratory cages or as a group in a large toy- and object-filled environment for 30 days. The spine density on dendrites of medium-sized spiny neurons in the dorsolateral striatum was then examined using the Golgi-Cox method. Rats reared in the complex environment displayed an increase of approximately 30% in spine density relative to those reared individually. These results demonstrate experience-dependent changes in neural structure in the striatum and suggest that the mechanisms for information storage in response to experience may be more widespread in the forebrain than previously believed.

Rats (Rattus norvegicus) modulate eating speed and vigilance to optimize food consumption: effects of cover, circadian rhythm, food deprivation, and individual differences.

The eating behavior of rats (Rattus norvegicus) given food pellets of specified size was examined as a function of environmental, circadian, and experiential influences. Eating times were shorter in lighted, exposed environments than in dark, covered environments, even though in novel, exposed conditions the rats made many scanning movements as they ate. Eating time also varied as a function of the circadian cycle in that eating times were shorter in the night portion of the day-night cycle. Finally, eating times decreased if rats were food deprived, and deprivation had a small but enduring influence. Within the tests there were differences in the eating times of individual rats that were not attributable to the experimental manipulations. That rats can optimize food intake by varying eating speed is discussed in relation to physiological regulation of feeding and to optimal foraging theory.