Brian H. Hallas

A neurobehavioral screening of the ckr mouse mutant: implications for an animal model of schizophrenia

A model of schizophrenia, the chakragati (ckr) mouse was serendipitously created as a result of a transgenic insertional mutation. The apparent loss-of-function of an endogenous gene produced mice that, when homozygous, displayed an abnormal circling behavior phenotype. To determine whether this phenotype could be corrected by atypical antipsychotics, we compared the effects of clozapine and olanzapine on rotational turns and hyperactivity. Both of these drugs successfully ameliorated circling behavior and hyperactivity in homozygous mice. The increased motor activity of these mutant mice was both qualitatively and quantitatively similar to that observed in wild-type animals treated with dizocilpine, an N-methyl-D-aspartate receptor antagonist that produces behaviors resembling positive symptoms of schizophrenia. Mice either homozygous or heterozygous for the mutation also displayed enlargement of the lateral ventricles, which was accompanied only in the homozygous genotype by a loss of individual myelinated axons in the striatum and agenesis of the corpus callosum. These structural brain deficits were selective in that the nigro-striatal dopamine system was normal in these homozygous mice. In addition, two types of interneurons in the neostriatum, namely those producing acetylcholine or nitric-oxide synthase were also devoid of significant structural abnormalities. These results indicate that the ckr mouse mutant could be used as a possible animal model to study the pathophysiology of schizophrenia and suggest possible strategies for treating the behavioral aspects of this brain disease.

Preliminary evidence for reduced social interactions in Chakragati mutants modeling certain symptoms of schizophrenia

Rodent models of schizophrenia provide powerful experimental tools for elucidating certain manifestations of the brain disease. The chakragati (ckr) mouse mutant, for instance, reproduces aberrant neuroanatomical and behavioral phenotypes observed in the corresponding human condition. To further investigate the utility of this mouse in the context of social behavior, we compared spontaneous behavioral activity and social interactions recorded during the subjective night among wild-type, heterozygous, and homozygous ckr mice. We found that both heterozygous and homozygous ckr animals failed to show appropriate norms of social behavior, including proximity, approach, huddling, and anogenital investigation in response to novel conspecifics. We further found that the anatomical distribution, topography, and connectivity of the neuropeptides oxytocin and vasopressin in the anterior hypothalamus did not differ among wild-type, heterozygous, or homozygous ckr animals. These latter findings suggest that although oxytocin and vasopressin influence social behavior, connectivity of such cells may not be phenotypically relevant for the observed social deficits seen in heterozygous and homozygous ckr mice. Collectively, ckr mice and their heterozygote kin are valuable experimental tools for pre-clinical studies involving disruptions of social behavior (e.g., social withdrawal).

Silent information regulator 1 mediates hippocampal plasticity through presenilin1

Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase directly implicated in protecting a wide range of organisms against internal and external metabolic insults. However, the identification of SIRT1-specific DNA targets that confer such protection have remained elusive. Using human cells, we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding presenilin1 (PSEN1), a protein intrinsically involved in the function of the γ-secretase protein complex. We also demonstrate that rats fed with resveratrol exhibit a significant increase in sirt1 and psen1 expression. Finally, dietary consumption of resveratrol also leads to an enhanced proliferative state of neuronal stem cells in the rat hippocampus. Our findings reveal a strong link between resveratrol-dependent SIRT1 signaling and hippocampal plasticity in the mammalian brain.

Weight loss dynamics during combined fluoxetine and olanzapine treatment

BackgroundFluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression. Determining drug-drug interactions, drug metabolism and pharmacokinetics is of particular interest for revealing potential liabilities associated with drug augmentation in special patient populations. In the current studies, we chronically administered fluoxetine and olanzapine in non-stressed rats to extend our previous findings regarding body weight dynamics.ResultsChronic fluoxetine (10 mg/kg) and olanzapine (5 mg/kg and 0.5 mg/kg) treatment decreased weight gain irrespective of olanzapine dosing. At the 10 mg/kg and 5 mg/kg dose, respectively, fluoxetine and olanzapine also significantly reduced food and water consumption. This pharmacodynamic event-related effect, however, was not observed at the 10 mg/kg and 0.5 mg/kg dosing paradigm suggesting differences in tolerability rates as a function of olanzapine dose. The decrease in weight gain was not associated with apparent changes in glucose metabolism as vehicle- and drug-treated rats showed undistinguishable serum glucose levels. The combination of fluoxetine and olanzapine in rats yielded drug plasma concentrations that fell within an expected therapeutic range for these drugs in psychiatric patients.ConclusionsThese data suggest that fluoxetine and olanzapine treatment decreases weight gain in rats; a pharmacodynamic event-related effect that differs considerably from what is observed in the clinical condition. The possibility of mismatched models regarding body weight changes during drug augmentation therapy should be seriously considered.

Magnetic resonance imaging and spectroscopy in a mouse model of schizophrenia.

Metabolic brain abnormalities, as demonstrated by (1)H-magnetic resonance spectroscopy, are common occurrences in adult schizophrenia. As mice share important biochemical and genomic similarities with humans, we tested whether brain metabolic abnormalities also occur in a transgenic mouse model of schizophrenia. In vivo(1)H-magnetic resonance spectroscopy at 4.7T of the chakragati mouse brain revealed abnormalities in relative levels of choline and N-acetylaspartate compounds. These results are consistent with a prior proposal that deficits in metabolite ratios may be common features of psychotic disorders. Thus, chakragati mice recapitulate certain aspects of the human disease phenotype and further support the utility of this animal model for understanding causal factors underlying uniquely human brain diseases.

Blood content modulates the induction of heat shock proteins in the neurovascular network.

Heat shock proteins are ubiquitous members of a family of molecular chaperones that protect various cell populations from injury. Up-regulation of heat shock proteins, particularly the 70 kDa species, bind selectively to denatured or partially damaged polypeptides that would otherwise perturb cell function and initiate cell death programs. In this regard, induction of heat shock proteins provides protection from cerebral ischemia in animal models of stroke. Endothelial cells, in particular, are intimately involved in the above protective event as these cells mount a stress response with induction of the 70 kDa heat shock protein. However, the coupling of heat shock proteins and the neurovascular response are not yet known. Here we show that blood content is an important factor in this stress response as rats devoid of blood content do not display a heat shock response in the microvasculature of the hippocampal formation. This lack of stress response, however, is reversed when rats are reperfused with exogenous rat or human blood content. We propose a new ischemic-sensing role for blood that serves to integrate information about protein-damaging conditions and heat shock protein levels in the neurovascular network. Further characterization of this sensing role could represent an attractive new approach to treatment of global ischemia and other microvascular pathologies.

Glutamate-Based Drugs for the Treatment of Clinical Depression

Clinical depression is a chronic, recurrent mood disorder that causes significant disability and disease burden throughout the world. Not surprisingly, there is an enormous demand for finding (a) appropriate medications and devices for treating the clinical symptoms and (b) the underlying molecular mechanisms of the disease. Currently, most therapeutic treatments of depression indirectly target the serotonin and norepinephrine systems of the brain, as these neurotransmitters have long been considered promising and mechanistically relevant to the etiology of mood disorders. However, selective serotonin reuptake inhibitors such as sertraline, fluoxetine and paroxetine do not always substantially improve clinical outcome, and when they do show efficacy, it takes weeks of treatment to achieve an appreciable clinical effect. These observations suggest that a serotonin and norepinephrine hypothesis of depression is incomplete at best, and that novel, rapid onset therapeutic options for depression must be considered. In this review, we highlight several potential new drugs for clinical depression based on recent discoveries about the neurotransmitter glutamate and its family of receptors. Moreover, we discuss the possibility that glutamate-based antidepressant drugs might affect covalent histone modifications including acetylation in areas of the brain (e.g., pre-frontal cortex, hippocampus) thought to be relevant for the pathogenesis of affective disorders. If so, histone hyperacetylation and thus chromatin remodeling might be important regulatory mechanisms underlying the effects of ketamine and other N-Methyl-D-Aspartate receptor antagonist drugs. Chromatin remodeling may represent a non-serotonin/norepinephrine therapeutic strategy for treatment of clinical depression, a strategy that may also be appropriate in the context of drug discovery and drug development.