Neuroanatomical Assessment of the Integrin β3 Mouse Model Related to Autism and the Serotonin System Using High Resolution MRI

The integrinβ3 (ITGβ3) gene has been associated with both autism and the serotonin system. The purpose of this study was to examine the volumetric differences in the brain of an ITGβ3 homozygous knockout mouse model compared with a corresponding wild-type mouse using high resolution magnetic resonance imaging and detailed statistical analyses. The most striking difference found was an 11% reduction in total brain volume. Moreover, 32 different regions were found to have significantly different relative volumes (percentage total brain volume) in the ITGβ3 mouse. A number of interesting differences relevant to autism were discovered including a smaller corpus callosum volume and bilateral decreases in the hippocampus, striatum, and cerebellum. Relative volume increases were also found in the frontal and parieto-temporal lobes as well as in the amygdala. Particularly intriguing were the changes in the lateral wings of the dorsal raphe nuclei since that nucleus is so integral to the development of many different brain regions and the serotonin system in general

Multiple-mouse Neuroanatomical Magnetic Resonance Imaging

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. MRI is an excellent modality for investigating genetically altered animals. It is capable of whole brain coverage, can be used in vivo, and provides multiple contrast mechanisms for investigating different aspects of neuranatomy and physiology. The advent of high-field scanners along with the ability to scan multiple mice simultaneously allows for rapid phenotyping of novel mutations

Semi-Automatic segmentation of multiple mouse embryos in MR images

<p>Abstract</p> <p>Background</p> <p>The motivation behind this paper is to aid the automatic phenotyping of mouse embryos, wherein multiple embryos embedded within a single tube were scanned using Magnetic Resonance Imaging (MRI).</p> <p>Results</p> <p>Our algorithm, a modified version of the simplex deformable model of Delingette, addresses various issues with deformable models including initialization and inability to adapt to boundary concavities. In addition, it proposes a novel technique for automatic collision detection of multiple objects which are being segmented simultaneously, hence avoiding major leaks into adjacent neighbouring structures. We address the initialization problem by introducing balloon forces which expand the initial spherical models close to the true boundaries of the embryos. This results in models which are less sensitive to initial minimum of two fold after each stage of deformation. To determine collision during segmentation, our unique collision detection algorithm finds the intersection between binary masks created from the deformed models after every few iterations of the deformation and modifies the segmentation parameters accordingly hence avoiding collision.</p> <p>We have segmented six tubes of three dimensional MR images of multiple mouse embryos using our modified deformable model algorithm. We have then validated the results of the our semi-automatic segmentation versus manual segmentation of the same embryos. Our Validation shows that except paws and tails we have been able to segment the mouse embryos with minor error.</p> <p>Conclusions</p> <p>This paper describes our novel multiple object segmentation technique with collision detection using a modified deformable model algorithm. Further, it presents the results of segmenting magnetic resonance images of up to 32 mouse embryos stacked in one gel filled test tube and creating 32 individual masks.</p

Degree of Retrograde Flow and Its Effect on Local Hemodynamics and Plaque Distribution in an Aortic Regurgitation Murine Model of Atherosclerosis

INTRODUCTION Previously, Zhou et al. Recently, Hoi et al. [2] used image-based Computational Fluid Dynamics (CFD) to demonstrate that maps of oscillatory shear index (OSI) and relative residence time (RRT) METHODS As detailed in [2] , the three-dimensional (3D) aortic geometry of a control mouse was reconstructed from micro-CT scans. The smoothed model, which closely resembled the original aortic lumen, was truncated at the celiac artery, thereby including only the aortic arch and DTA

Cerebral asymmetries in 12-week-old C57Bl/6J mice measured by magnetic resonance imaging

Asymmetries of multiple components of the rodent cerebrum have been described at various levels of organization. Yet, despite its ubiquitous nature, many confusing and sometimes contradictory reports regarding structural asymmetries in the rodent brain have been published. There is a need, therefore, for a whole-brain imaging analysis technique for asymmetry studies that is both accurate, reproducible and robust. To this end, a comprehensive three-dimensional examination of differences in brain structure in an inbred mouse strain was undertaken. The goal of this study was thus to use high-resolution magnetic resonance imaging to assess structural asymmetries in the adult C57Bl/6J mouse brain. Fixed brain T2-weighted images of 20 male C57Bl/6J mice were acquired on a 7T scanner at 32 μm isotropic resolution. We used voxel-based analyses to examine structural asymmetries throughout the whole mouse brain. The striatum, medial-posterior regions of the thalamus, and motor, sensorimotor, and visual cortex were found to be asymmetrical. The most significant asymmetry was found in the hippocampus and, specifically, the dentate gyrus. In each case, the left region was larger than the right. No other regions of the mouse brain showed structural asymmetry. The results in the dentate gyrus were confirmed using stereology, revealing a correlation of r = 0.61 between magnetic resonance and stereological measures. Hippocampal, along with cortical asymmetry, has been discussed repeatedly in the literature, yet a clear pattern of directionality, until this point, has not been described. The findings of asymmetry in the striatum and absence of asymmetry in the rest of the brain are novel and show the advantage of using the whole-brain three-dimensional techniques developed herein for assessing asymmetry

Dosage-Dependent Phenotypes in Models of Human 16p11.2 Lesions Found in Autism

Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a “behavior trap” phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders

Regionally reduced brain volume, altered serotonin neurochemistry, and abnormal behavior in mice null for the circadian rhythm output gene Magel2.

Magel2 belongs to the MAGE/necdin family of proteins, which have roles in cell cycle, differentiation, and apoptosis. The Magel2 gene is expressed in various brain regions, most notably the hypothalamus. Mice with a targeted deletion of Magel2 display hypoactivity, blunted circadian rhythm, decreased fertility, and increased adiposity. The human ortholog, MAGEL2, is one of a set of paternally expressed, imprinted genes inactivated in most cases of Prader-Willi syndrome, a complex neurodevelopmental disorder. To explore the role of Magel2, brain morphology, brain neurochemistry, and behavior were measured in Magel2-null mice. Brain volume was reduced in specific regions, particularly in the parieto-temporal lobe of the cerebral cortex, the amygdala, the hippocampus, and the nucleus accumbens, as measured by quantitative magnetic resonance imaging. Abnormal neurochemistry was detected in brain samples from adult mice, consisting of decreased serotonin and 5-hydroxyindoleacetic acid in the cortex and the hypothalamus, and decreased dopamine in the hypothalamus. Magel2-null mice displayed relatively normal motor and learning abilities, but exhibited abnormal behavior in novel environments. This study lends support to the important role of the circadian rhythm output gene Magel2 in brain structure and behavior. Ó 2009 Wiley-Liss, Inc. Key words: Prader-Willi syndrome; anxiety; magnetic resonance imaging; circadian rhythm; imprinting INTRODUCTION Magel2 is a member of the Type II melanoma-associated antigen gene (MAGE) protein family, which share a protein-protein interaction domain called the MAGE homology/conserved domain 1085 Neuropsychiatric Genetics 1995]. The MAGE homology domain of several Type II MAGE proteins (necdin, MAGE-G1, MAGED1) binds to multiple transmembrane receptors involved in intracellular signaling MAGEL2 and NDN, the gene that encodes the MAGE protein necdin, are among a small set of genes that are typically inactivated in Prader-Willi syndrome (PWS). PWS is a congenital disorder characterized by symptoms of varying severity among affected individuals: intellectual disability, hypotonia, short stature, childhood-onset hyperphagia often leading to obesity, excessive sleepiness, neuroendocrine abnormalities, and incomplete sexual development We recently described a mouse strain carrying a gene-targeted lacZ insertion into the Magel2 locus, creating a null Magel2 allele MATERIALS AND METHODS Magel2-Null Mice All animal studies were conducted in accordance with the Canadian Council on Animal Care Guidelines and Policies with approval from the local Animal Policy and Welfare Committees. Magel2-null mice carry a replacement of the Magel2 gene with a LacZ reporter cassette, resulting in complete loss of Magel2 function in heterozygotes with a paternally derived gene-targeted allele Sample Preparation for MRI Magel2-null mice (n ¼ 6) and their wild-type littermates (n ¼ 6) were anesthetized at 26 weeks of age with a combination of Ketamine (100 mg/kg, Pfizer, Kirkland, QC, Canada) and Rompun (20 mg/kg, Bayer, Inc., Toronto, ON, Canada) via intraperitoneal injection. A previously described sample preparation protocol for scanning was used with slight modifications MRI Image Acquisition A multi-channel 7.0-T MRI scanner (Varian, Inc., Palo Alto, CA) with a 6 cm inner bore diameter insert gradient set was used to acquire anatomical images of brains within skulls. Prior to imaging, the samples were removed from the contrast agent solution, blotted and placed into 13 mm diameter plastic tubes filled with a protonfree susceptibility-matching fluid 3 M Corp., St. Paul, MN). Three custom-built, 14 mm diameter solenoid coils with a length of 18.3 mm and over wound ends were used to image three brains in parallel. Parameters used in the scans were optimized for gray/white matter contrast: a T2-weighted, 3D fast spin-echo sequence, with TR/TE ¼ 325/32 msec, four averages, field-of-view 14 mm  14 mm  25 mm and matrix size ¼ 432  432  780 giving an image with 32 mm isotropic voxels. Total imaging time was 11.3 hr . Image Processing The 32 mm isotropic resolution T2-weighted MRI scans were nonlinearly aligned to a three dimensional atlas of the mouse brain with 62 structures identified The end result was that all 12 scans were deformed into exact alignment with each other in an unbiased fashion. This allowed for the analysis of the deformations needed to take each mouse&apos;s anatomy into this final atlas space, the goal being to model how the deformation fields relate to genotype. Correspondence with the 3D atlas was obtained by nonlinear alignment of the final stage average MRI with the 40-mouse average MRI upon which the atlas is based MRI Analysis Local differences in brain shape related to genotype were assessed by analysis of the deformation fields Neurochemical Analysis Brain regions were dissected from embryonic or adult Magel2-null or wild-type littermate control mice, snap frozen on dry ice, then stored at À80 C. Brain samples were processed for HPLC combined with fluorescence detection to measure levels of biogenic amines (noradrenaline (NA), dihydroxyphenylacetic acid (DOPAC), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), serotonin (5-HT) and amino acids (Trp, Asp, Glu, Asn, Ser, Gln, Gly, Taur, Ala, GABA)) as described Behavioral Analysis Male Magel2-null mice and their control littermates were tested in the following order at the Centre for Modeling Human Disease: modified SHIRPA for general health, appearance, and neurological reflexes The contextual and cued fear conditioning test was performed using the Video Fear Conditioning system (Med Associates, St. Albans, VT) essentially as described The custom apparatus for the beam test is made up of two platforms (25 cm  35 cm) that are connected with a 90 cm long round beam (18 mm diameter) suspended 50 cm above the floor. One platform was brightly illuminated while the opposite platform MERCER ET AL. 1087 was dark and contained a box providing an enclosed safety area for the mouse. Four consecutive training trials to assist the mouse in navigating the beam were performed on the first day. On the second day, a single trial that recorded the latency to traverse the beam and the number of times the hind feet slipped off was performed. The one-trial object recognition task Behavioral data were analyzed statistically by t-test except the horizontal and vertical activity profile, the 3-day Rotarod test, and the fear-conditioning test, which were analyzed by two-way ANOVA with Bonferroni post-tests, using GraphPad Prism. Probabilities &lt;0.05 were deemed significant. RESULTS Expression of Magel2 in the Adult Mouse Brain We previously outlined expression of Magel2 in the embryonic brain by RNA in situ hybridization General Behavior and Health of Magel2-Null Mice No overt differences in the acquisition of developmental milestones (e.g., physical development, rooting reflex, righting reflex, forelimb/hind limb grasping, or locomotor behavior Neuroanatomical Abnormalities in Magel2-Null Mice Measured by MRI No gross abnormalities in sections of the Magel2-null mouse brains were detected by Nissl staining (not shown). To examine the brain more finely and without the confounding effect of removal from the skull, very high resolution MRI combined with computer analysis was performed. MRI analysis revealed reduced brain volume in the mutant mice (3.4% smaller than control brain, P &lt; 0.01). We used a statistical map of the Jacobian determinant that illustrates the expansion and contraction of tissue based on genotype, to find regions of significant change. In order to account for an inflated amount of false positive findings due to the number of statistical tests employed, the FDR technique was applied The reduced concentration of serotonin or dopamine could be caused by a reduction in the number of dopaminergic or serotonergic neurons in the Magel2-null mouse brains. To examine this possibility, we first examined the location and number of dopaminergic neurons (immunoreactive with an antibody against TH and visualized by confocal microscopy) in the hypothalamus in adult and Magel2-null male mouse brain sections. We found a comparable number of positively staining neurons in both genotypes, and no differences in the appearance of the TH-positive neurons groups in the pre-optic region, the medial basal region, or the medial dorsal region of the hypothalamus (A11-A15 dopaminergic cell groups, Suppl. AMERICAN JOURNAL OF MEDICAL GENETICS PART B with an anti-5-HT antibody revealed no differences in the location or number of serotonergic neurons in the cell groups in the brain stem (Suppl. Magel2-Null Tests of Anxiety and Learning The elevated plus maze is a more specific test of anxiety in a novel environment. The time spent in the open or closed arms, time spent on the end of the open arms and on the central platform, time spent freezing in the open and freezing in the center, the number of passes between closed arms, the number of risk assessments, and the number of head dips were all measured, but no significant differences between genotypes were detected (data not shown). We then used a Pavlovian fear-conditioning test that measures percent of time spent with total lack of movement (freezing) after an aversive stimulus, and the learning associated with this stimulus. This test also models anticipatory anxiety, and requires a combination of amygdalar and hippocampal function. Each mouse was acclimatized in a test context, then a 30 sec auditory tone was used as the conditioned stimulus paired with an aversive unconditioned stimulus, in this case a 2 sec mild foot shock at the end of the tone. After conditioning, either the test context or the tone typically elicit a state of fear even in the absence of the foot shock, in a normal mouse. This fear is manifested as freezing, and is used to measure learning when assessed after 24 hr. The Magel2-null mice tended towards an increased amount of time spent freezing during the baseline measurement on Day 1 (1.2 AE 0.7% for control mice, 12.4 AE 5.7% for the Magel2-null mice, P &lt; 0.09, all values expressed as mean AE standard error of the mean (SEM), Magel2-Null Mice Display Altered Behavior in Novel Environments As a further test to discriminate anxiety from learning, we performed a set of tests that measure reactions to novel objects in an independent cohort of male and female mice that were na€ ıve to behavioral testing. In a one-trial object recognition task, each Latency to fall from an accelerating Rotarod during a single test is significantly increased in the Magel2-null mice; **P &lt; 0.05. E: Latency to fall from an accelerating Rotarod increases for both genotypes over three consecutive days indicating normal motor learning. Latency to fall is significantly increased in the Magel2-null mice (two-way ANOVA, main effect of genotype P &lt; 0.0006). AMERICAN JOURNAL OF MEDICAL GENETICS PART B FIG. 3. Fear conditioning test and novel object scenarios reveal abnormal behavior in Magel2-null mice. A: Magel2-null mice freeze more than wildtype (WT) control mice in the test context at baseline and after the auditory tone, but have similar freezing rates after the foot shock. On Day 2, freezing in the familiar test context was not different between genotypes, but in contrast, Magel2-null mice freeze more than control at baseline in the altered context, pre-tone. Also on Day 2, the net amount of freezing in the novel context either before (pre-tone) or after (tone) the auditory tone was not different between genotypes. Data are expressed as mean AE SEM. Two-way ANOVA detected a main effect of genotype across the six freezing measurements (P &lt; 0.0001). The fold change (x) in freezing during fear conditioning is also presented as a ratio of the means. Fold changes in the test context (tone, shock, day 2 context) are compared to baseline. Fold changes in the altered context after the tone are compared to the pre-tone measurement. Magel2-null mice show a blunted fear reaction to either the test context or to the tone. B: Female Magel2-null display increased exploratory behavior when placed in a cage with two novel objects, with decreased latency to reach 38 sec total exploration time. Data are expressed as mean AE SEM, **P &lt; 0.05. C: Control mice of both sexes and male Magel2-null mice spend more time with the novel object than with the familiar object, measured after 5 min and after 24 hr, and presented as a discrimination index (the difference between the time with the novel object and the time with familiar object divided by the total time). Magel2-null female mice show no preference for a novel object after 3 min (DI ¼ 0, **P &lt; 0.05). D: Male mice of both genotypes buried similar numbers of marbles over the three min. test interval. In contrast, female Magel2-null mice buried significantly fewer marbles than controls; **P &lt; 0.05. E: Control mice consume slightly less food during their first to days in an Accuscan chamber with powdered food, but increase food consumption to normal levels by day 3 in the chamber. In contrast, Magel2-null mice have substantially reduced food intake when initially placed in the Accuscan chamber, and never attain normal levels of food intake. MERCER ET AL. 1093 mouse was removed from the home cage and acclimatized to the test cage in which two objects (e.g., plastic 15 ml tube, 10 ml syringe) were placed. The total length of time needed to accumulate 38 sec of active object exploration was recorded. Magel2-null female mice explored the objects more actively than their control littermates, accumulating 38 sec of exploration time within 141 AE 26 sec, while the control female mice required twice as long to accumulate the total exploration time (321 AE 53 sec, P &lt; 0.02) Wild-type mice typically spend 70% of their time with the novel object and 30% with the familiar object under this paradigm Our hypothesis that Magel2-null mice tend to avoid novel objects and are anxious in novel environments is supported by observations we made during a previous feeding study. In this experiment, male mice were placed in a chamber with a powdered standard chow dispenser that measured hourly food consumption over 5 days Additional Tests of Behavior Mice normally exhibit self-grooming behavior, and pathological self-grooming or excessive grooming of cage mates has been interpreted as evidence of obsessive-compulsive tendencies in mice DISCUSSION Magel2 belongs to the MAGE family of proteins, and is most closely related to MAGED1/NRAGE and necdin. Studies in cell culture and in mice have implicated necdin in neural differentiation and cell cycle exit, and structural and function deficits in the nervous system have been identified in necdin-null mice Magel2-Null Mice Have Reduced Brain Volume and Reduced Neurotransmitter Levels in Discrete Regions of the Brain Subtle changes in regional brain volume have been described in a variety of congenital and progressive genetic disorders, most 1094 AMERICAN JOURNAL OF MEDICAL GENETICS PART B prominently in human and mouse studies of schizophrenia It is difficult to establish a cause and effect relationship between neurochemical imbalances and behavior in mice, particularly as total levels combine the intracellular and extracellular pools of the neurotransmitters. For example, many studies implicating serotonin in mood and behavior use surrogate markers, such as 5-HT or 5-HIAA levels in cerebrospinal fluid or platelets, examine the activation of serotonin receptors after pharmacological intervention, or the effects of depletion of the serotonin precursor tryptophan on behavior. Nonetheless, many studies have linked altered serotonergic and dopaminergic pathways with psychiatric disorders, most notably depression, anxiety, and self-injurious or obsessive behavior Magel2-Null Mice Are Hypoactive and React Abnormally to Novel Environments We performed assays in Magel2-null mice designed to measure anxiety-like behavior, locomotion, balance, neuromuscular function, learning, and memory. Behavioral tests in animal models can provide surrogate markers for normal or pathological human behavior. In transgenic animal studies, interacting deficits in different processes can influence performance in behavior tests Balance and strength were not impaired by the Magel2 mutation, as evidenced by normal or improved function in rearing in the open field, time to cross in the beam test, increased latency to fall from the Rotarod, and equivalent time spent struggling in the tail suspension test. One interpretation of the increased latency to fall from the Rotarod is that the Magel2-null mice have normal strength and balance, as supported by the other tests of motor function, but have increased motivation not to fall, consistent with their abnormal reaction to other novel environments. We did however observe a significant reduction in open field activity in Magel2-null mice, consistent with previous findings that used running wheels to monitor 24 hr activity of Magel2-null mice MERCER ET AL. 1095 We found no evidence for learning or long-term memory deficiencies in the 3-day Rotarod test, the 24 hr novel object preference test, or the 24 hr fear-conditioning test. There was an increase in freezing in the Magel2-null mice on day 2 of the fear conditioning test, suggesting they are not grossly impaired in amygdalar or hippocampal functions required for conditioned learning over 24 hr. The interpretation of learning in the fearconditioning test was complicated by the high baseline freezing rates in the Magel2-null mice, which led to a smaller fold increase in freezing either to the context or to the tone on Day 2. The conditioned fear test revealed a significant difference between genotypes not related to learning or memory: male Magel2-null mice have increased time spent freezing under baseline conditions, indicating increased anxiety in the test chamber. It is unlikely that reduced activity accounts for this increase in freezing during the 2 min baseline measurement, as there was only minimal difference in horizontal or vertical activity between genotypes in the first 5 min of the open field test. Rather, there was a progressive decline in activity of the Magel2-null mice over the following 25 min in the open field. In a test used as a proxy for anxiety in rodents, we found no inter-genotype difference in marble burying activity in male mice, nor was there any difference in the time male mice spent with objects in the cage. In contrast, female Magel2-null mice spent more time exploring objects placed in a cage, did not display novel object preference when placed back into the test chamber after a 5 min interval, and were less likely to bury marbles placed on the surface of the bedding. In summary, the object-based tests with the female mice suggest a combination of poor short-term memory for novel objects and decreased motivation to manipulate objects in the cage. Interestingly, sex-specific differences in behavioral responses to novel objects were also observed in a serotonin-depletion mouse model of developmental brain disorders Abnormalities of Brain and Behavior: Comparison With PWS In PWS, psychiatric symptoms often develop during childhood and can include mood instability, obsessive-compulsive disorder, autism spectrum disorder, cognitive rigidity, anxiety, and addictive behavior towards to food and other substances Although the extrapolation of murine studies to human behavior must be approached with caution, studies of genetically engineered mice have successfully recapitulated the fundamental behavioral aspects of the respective human genetic disorder in many cases Almost all individuals with PWS lack expression of multiple genes, including loss of function of MAGEL2 and necdin, and most PWS candidate genes are moderately to highly expressed in the brain . It is unclear how much contribution to the PWS phenotype is made by each of the deleted genes. Comparison with other mouse strains carrying individual PWS gene deletions may be informative, although few behavioral studies have been performed to date. We previously showed that mice lacking necdin are underweight at birth A report of a child with atypical PWS carrying a chromosome deletion of 175 kb AMERICAN JOURNAL OF MEDICAL GENETICS PART B RNAs (HBII-85) (e.g., ACKNOWLEDGMENT

Delayed myelination in a mouse model of fragile X syndrome

Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1 -3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80 -85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRa1/NG21 oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome

Abnormalities in brain structure and behavior in GSK-3alpha mutant mice

<p>Abstract</p> <p>Background</p> <p>Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by two genes that generate two related proteins: GSK-3α and GSK-3β. Mice lacking a functional GSK-3α gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3α KO mice by using a well-established battery of behavioral tests together with neurochemical and neuroanatomical analysis.</p> <p>Results</p> <p>Similar to the previously described behaviours of GSK-3β^+/-mice, GSK-3α mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3α gene was associated with: decreased locomotion and impaired motor coordination, increased grooming activity, loss of social motivation and novelty; enhanced sensorimotor gating and impaired associated memory and coordination. GSK-3α KO mice exhibited a deficit in fear conditioning, however memory formation as assessed by a passive avoidance test was normal, suggesting that the animals are sensitized for active avoidance of a highly aversive stimulus in the fear-conditioning paradigm. Changes in cerebellar structure and function were observed in mutant mice along with a significant decrease of the number and size of Purkinje cells.</p> <p>Conclusion</p> <p>Taken together, these data support a role for the GSK-3α gene in CNS functioning and possible involvement in the development of psychiatric disorders.</p