Volume 1, Issue 3

Based on evidence suggesting that deep brain stimulation (DBS) may promote certain cognitive processes, we have been interested in developing DBS as a means of mitigating memory and learning impairments in Alzheimer’s disease (AD). In this study we used an animal model of AD (TgCRND8 mice) to determine the effects of high-frequency stimulation (HFS) on non-amyloidogenic α-secretase activity and DBS in short-term memory. We tested our hypothesis using hippocampal slices (in vitro studies) from TgCRND8 mice to evaluate whether HFS increases α-secretase activity (non-amyloidogenic pathway) in the CA1 region. In a second set of experiments, we performed in vivo studies to evaluate whether DBS in midline thalamic region re-establishes hippocampal dependent short-term memory in TgCRND8 mice. The results showed that application of HFS to isolated hippocampal slices significantly increased synaptic plasticity in the CA1 region and promoted a 2-fold increase of non-amyloidogenic α-secretase activity, in comparison to low frequency stimulated controls from TgCRND8 mice. In the in vivo studies, DBS treatment facilitated acquisition of object recognition memory in TgCRND8 mice, in comparison to their own baseline before treatment. These results provide evidence that DBS could enhance short-term memory in the CA1 region of hippocampus in a mouse model of AD.

Type 1 myotonic dystrophy (DM1) is an autosomal dominant disorder caused by a CTG repeat expansion. RNA containing expanded CUG repeats does not leave the nucleus, but accumulates in discrete nuclear foci which sequester the human muscleblind-like (MBNL) proteins. We have examined buccal cells from 15 adult DM1 patients and 7 control non-DM patients to determine whether nuclear foci can be detected by either immunostaining for MBNL1 protein or fluorescent in situ hybridisation (FISH) for the CUG repeat RNA. Both methods detected nuclear foci in all three early-onset patients, but only in a minority of 12 less severe DM1 patients. There were no false-positive results in the 7 controls. Although the method does not reliably identify all DM1 patients, it may prove useful as a rapid test for severe congenital DM1 in floppy babies.

Sporadic Alzheimer’s disease (sAD) is associated with decreased glucose/energy metabolism in the brain. The majority of glucose utilization in the brain appears to be mediated through glucose transporter protein 1 and 3 (GLUT1 and GLUT3). Deficiency of GLUT1 and GLUT3 in the brain has been found in sAD patients post mortem; however this is not unique to the disease as it is associated with different clinical syndromes as well. In line with recent findings that insulin resistant brain state precedes and may possibly cause sAD, an experimental sAD model based on the central application of the streptozotocin (STZ-icv rat model), which is a selective GLUT2 substrate, has drawn attention to the possible significance of the brain GLUT2 in sAD etiopathogenesis. Important steps in the GLUT2 and sAD interplay are reviewed and discussed. It is concluded that increased vulnerability of GLUT2 expressing neurons may be involved in development of sAD.

Serotonin (5-hydroxytryptamine, 5-HT) is a signalling molecule involved in many brain functions as well as in a variety of psychiatric conditions, including suicidal behaviour. Tryptophan hydroxylase (TPH), the rate-limiting enzyme of 5-HT biosynthesis, plays a critical role in 5-HT metabolism and thus in the regulation of 5-HT neurotransmission. There are two isoforms of TPH, so-called peripheral (TPH1) and neuronal (TPH2), encoded by the two distinct genes. TPH1 is abundant in the peripheral tissues, while TPH2 was detected exclusively within the nervous system. Since its discovery in 2003, TPH2 gene has attracted great interest as a potential factor contributing to diathesis of suicidal behaviour. However, initial positive findings indicating an association of TPH2 genetic variants with suicide have not been replicated consistently. Here we provide an overview of published studies to date, that have evaluated the contribution of TPH2 gene to the etiopathogenesis of suicidal behaviour.

The nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

Previous studies have shown deficits in the perception of static emotional facial expressions in individuals with autism spectrum disorders (ASD), but results are inconclusive. Possibly, using dynamic facial stimuli expressing emotions at different levels of intensities may produce more robust results, since these resemble the expression of emotions in daily life to a greater extent. 30 Young adolescents with high-functioning ASD (IQ>85) and 30 age- and intelligence-matched controls (ages between 12 and 15) performed the Emotion Recognition Task, in which morphs were presented on a computer screen, depicting facial expressions of the six basic emotions (happiness, disgust, fear, anger, surprise and sadness) at nine levels of emotional intensity (20–100%). The results showed no overall group difference on the ERT, apart from a slightly worse performance on the perception of the emotions fear (p<0.03) and disgust (p<0.05). No interaction was found between intensity level of the emotions and group. High-functioning individuals with ASD perform similar to matched controls on the perception of dynamic facial emotional expressions, even at low intensities of emotional expression. These findings are in agreement with other recent studies showing that emotion perception deficits in high-functioning ASD may be less pronounced than previously thought.

Exon-specific anti-dystrophin antibodies are used to monitor the success of treatments for Duchenne muscular dystrophy that aim to restore the missing dystrophin protein. Dystrophin is a large cytoskeletal protein encoded by 79 exons and expressed mainly in muscle. Most cases of Duchenne and Becker muscular dystrophies are caused by genetic deletion of one or more exons. In-frame deletions permit some synthesis of internally-deleted dystrophin and cause the milder Becker form, while out-of-frame deletions in the severe Duchenne form result in early stop-codons and no functional dystrophin synthesis. In this study, we describe the production of ten new monoclonal antibodies against a rod region encoded by exons 55–59 and their mapping to specific dystrophin exons, thus filling a major gap in the spectrum of available antibodies. The antibodies have already been applied in a published clinical trial of a drug treatment for Duchenne muscular dystrophy.

The dopaminergic system is of crucial importance for understanding human behavior and the pathogenesis of many psychiatric and neurological conditions. The majority of studies addressing the localization of dopamine receptors (DR) examined the expression of DR in neurons, while its expression, precise anatomical localization and possible function in glial cells have been largely neglected. Here we examined the expression of D2-like family of DR in neuronal and glial cells in the normal human brain using immunocytochemistry and immunofluorescence. Tissue samples from the right orbitomedial (Brodmann’s areas 11/12), dorsolateral (areas 9/46) and dorsal medial (area 9) prefrontal cortex were taken during autopsy from six subjects with no history of neurological or psychiatric disorders, formalin-fixed, and embedded in paraffin. The sections were stained using novel anti-DRD2, anti-DRD3, and anti-DRD4 monoclonal antibodies. Adjacent sections were labeled with an anti-GFAP (astroglial marker) and an anti-CD68 antibody (macrophage/microglial marker). The pyramidal and non-pyramidal cells of all three regions analyzed had strong expression of DRD2 and DRD4, whereas DRD3 were very weakly expressed. DRD2 were more strongly expressed in layer III compared to layer V pyramidal neurons. In contrast, DRD4 receptors had a stronger expression in layer V neurons. The most conspicuous finding was the strong expression of DRD2, but not DRD3 or DRD4, receptors in the white matter fibrous astrocytes and in layer I protoplasmic astrocytes. Weak DRD2-immunoreactivity was also observed in protoplasmic astrocytes in layers III and V. These results suggest that DR-expressing astrocytes directly participate in dopaminergic transmission of the human prefrontal cortex.

Social deprivation leads to various neuroanatomical, neuropsychological and behavioral disturbances in humans as well as in experimental animals. Shared characteristics of socially deprived subjects and subjects with autism have been documented. The aim of this study was to analyze early development of communication in institutionalized (INST) children (12–24 months) in comparison with age- and sexmatched group of typically developing (TD) children and a group of children with autism spectrum disorders (ASD). Our findings show that both socially deprived (INST) children and ASD children display delayed pattern of development in social, speech and symbolic domains. However, although INST children display significant developmental delay and share some features with ASD children, they have a qualitatively different developmental pattern of social communication in comparison to children with ASD. The results of this study indicate that growing up in an institution and lack of social and environmental stimuli influences development of skills that are fundamental for early speech and language development.

The subpial granular layer (SGL) is a transient accumulation of tangentially migrating small granular neurons in the marginal zone of the developing fetal neocortex. It has recently attracted attention as a possible additional source of future cortical interneurons, or even as a putative precursor pool for generation of Cajal-Retzius cells. The discovery of the SGL is generally attributed to Otto Ranke and it is usually claimed that the SGL is specific for human brain. The aim of this review is: (1) to demonstrate that the first to observe SGL in the human cerebral cortex was not Otto Ranke in 1910, but Franz Boll in 1874; (2) to provide an English translation of Ranke’s original description of the SGL and thus demonstrate that he described the SGL in both human and animal brain; and (3) to provide a concise review of current studies concerning the developmental fate and possible functions of the transient fetal SGL.