Band 1, Heft 2

Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with selective neuronal cell death. Abnormal aggregation of huntingtin protein with polyQ expansion has been shown to be causally linked to HD. Grape seed polyphenolic extract (GSPE) is a natural compound that has previously been shown to interfere with aggregations of proteins involved in neurological disorders, such as amyloid beta peptides (Aβ) and Tau protein. In this study we found that GSPE treatment significantly inhibits polyQ aggregation in phaeochromocytoma (PC)-12 cell line containing an ecdysone-inducible protein comprising the first 17 amino acid of huntingtin plus 103 glutamines fused with enhanced GFP. In vivo feasibility studies using the Q93httexon1 drosophila model of HD, we extended our in vitro evidence and found that flies fed with GSPE had a significantly improved lifespan compared to the control flies. Using the R6/2 rodent model of HD, we found that oral administration of 100 mg/kg/day GSPE (equivalent to 500mg per day in human) significantly attenuated the motor skill decay as well as extended the lifespan in the R6/2 mice relative to vehicle-control mice. Collectively, our studies strongly suggest that GSPE might be able to modulate the onset and/or progression of HD.

Research to date has indicated that cAMPspecific PDEs, particularly the members of PDE4 family, play a crucial role in the pathogenesis of CNS injury and neurodegeneration by downregulating intracellular levels of cAMP in various cell types. Reduced cAMP signaling results in immune cell activation, inflammation, secondary tissue damage, scar formation and axon growth failure, ultimately leading to an exacerbation of injury, the prevention of endogenous repair and limited functional recovery. Although inhibition of cAMPspecific-PDE activity through the use of drugs like Rolipram has been shown to reverse these deficiencies and mediate neurorepair, an inability to develop selective agents and/or reduce dose-limiting side-effects associated with PDE4 inhibition has hampered their clinical translation. Recent work with more selective pharmacological inhibitors of cAMP-specific PDEs and molecular targeting approaches, along with improved understanding of the basic biology and role of PDEs in pathological processes may enable this promising therapeutic approach to advance clinically and have a similar impact on CNS injury and disease as PDE5 inhibitors have had on the treatment of sexual dysfunction.

Mutations of the neurofibromin gene (NF1) cause neurofibromatosis type 1 (NF1), a disease in which learning disabilities are common. Learning deficits also are observed in mice with a heterozygous mutation of Nf1 (Nf1 +/−). Dysregulation of regulated neurotransmitter release has been observed in Nf1 +/− mice. However, the role of presynaptic voltage-gated Ca2+ channels mediating this release has not been investigated. We investigated whether Ca2+ currents and transmitter release were affected by reduced neurofibromin in Nf1 +/− mice. Hippocampal Ca2+ current density was greater in neurons from Nf1 +/− mice and a greater fraction of Ca2+ currents was activated at less depolarized potentials. In addition, release of the excitatory neurotransmitter, glutamate, was increased in neuronal cortical cultures from Nf1 +/− mice. Dendritic complexity and axonal length were also increased in neurons Nf1 +/− mice compared to wild-type neurons, linking loss of neurofibromin to developmental changes in hippocampal axonal/cytoskeletal dynamics. Collectively, these results show that altered Ca2+ channel density and transmitter release, along with increased axonal growth may account for the abnormal nervous system functioning in NF1.

Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by subacute onset of headache, decreased alertness, vomiting, seizures, visuoperceptual disturbances, together with bilateral white matter lesions in posterior brain regions on brain imaging. The most frequently associated conditions related to RPLS are arterial hypertension and the use of immunosuppressive or cytotoxic treatment. T2-, Fluid Attenuation Inversion Recovery (FLAIR), and Apparent Diffusion Coefficient (ADC)-weighted magnetic resonance imaging (MRI) reveal hyperintensities in parietooccipital white matter but grey matter and other regions including frontal and temporal lobes, brainstem, cerebellum, basal ganglia, or even spinal cord may also be involved. According to ADC findings, the underlying pathophysiologic mechanism is probably one of vasogenic (rather than cytotoxic) oedema. These MRI findings help in differentiating RPLS from ischaemic events and other diseases resembling RPLS. Failure of cerebral autoregulation, endothelial dysfunction, disrupted blood-brain barrier, vasospasm, and direct toxic drug effects may all play a role in the pathophysiology of RPLS. Treatment consists of discontinuation of the causal drug, treatment of high blood pressure, and antiepileptic therapy. Clinical recovery and regression of radiological abnormalities are typically seen after early treatment. However, delay in diagnosis and treatment can result in irreversible brain damage, often in association with complicating cerebral infarction or haemorrhage.

Morphometric studies of the corpus callosum suggest its involvement in a number of psychiatric conditions. In the present study we introduce a novel pattern recognition technique that offers a point-bypoint shape descriptor of the corpus callosum. The method uses arc lengths of electric field lines in order to avoid discontinuities caused by folding anatomical contours. We tested this technique by comparing the shape of the corpus callosum in a series of dyslexic men (n = 16) and age-matched controls (n = 14). The results indicate a generalized increase in size of the corpus callosum in dyslexia with a concomitant diminution at its rostral and caudal poles. The reported shape analysis and 2D-reconstruction provide information of anatomical importance that would otherwise passed unnoticed when analyzing size information alone.

Myelin associated glycoprotein (MAG) is an oligodendrocyte-derived gene whose expression is decreased in schizophrenia. Several measures of white matter integrity appear abnormal in schizophrenia, specifically in the anterior cingulate gyrus. We studied mice lacking MAG as a potential model of dysmyelination. Using the stereological “Space Balls” method, we estimated myelinated fiber length density in the cingulum bundle in adult knockout and control mice. We performed diffusion anisotropy imaging in these animals, measuring fractional anisotropy (FA) in a region of the cingulum bundle. We found no differences in cingulum myelinated fiber length density between the two groups, although we did note an age-related decrease regardless of genotype. No differences were noted in FA either, but an age-related decrease was seen as well. These findings imply that MAG dysfunction alone is not sufficient to cause the white matter alterations seen in schizophrenia.

The most common primary CNS tumors are gliomas, where other than a few subtypes such as oligodendrogliomas, the survival has remained unchanged despite advances in surgical, chemo- and radiation therapy, especially for the most malignant and common glioma; glioblastoma multiforme (GBM). Recent novel therapies like immuno- and gene therapy have shown some promise in existing pre-clinical models, but have failed to demonstrate therapeutic benefit in patients. The reason(s) for such failures include our incomplete understanding of the molecular pathogenesis of these tumors and also due to testing of novel biological therapies in less than ideal pre-clinical models, which for the most part have included xenografts established in mice from glioma cell lines or patient explants. Transgenic mouse models offers an opportunity to develop and utilize an easily replenished, reproducible, manipulated spontaneous and more appropriate pre-clinical model of human cancers. Here we highlight on how mouse models are generated using several techniques and how mouse models have come to the forefront to address several issues such as identifying novel tumour modifier genes of central and peripheral nervous system tumours. Lastly we discuss how mouse models may provide an invaluable tool in pre clinical drug screening and testing.

In a biological sense an individual’s life is all about survival and reproduction. Beside the selection of a mate, the mutual commitment of a parent to sustain an infant through a period of dependency is amongst the most important aspects of natural selection. Here we review how the highly conserved circuitry of key midbrain and hypothalamic structures, and limbic and frontal cortical regions support these processes, and at the same time are involved in shaping the offspring’s emotional development and behavior. Many recent studies provided new findings on how attachment behavior and parental bonding is promoted and maintained through genetic and epigenetic influences on synaptic plasticity of mirror neurons and various neuropeptide systems, particularly oxytocinergic, and how these systems serve to link social cues to the brain reward system. Most of this evidence suggests that stress, early parental deprivation and lack of care during the postnatal period leads to profound and lasting changes in the attachment pattern and motivational development with consequent increased vulnerability of the mesocortical and mesolimbic dopamine-associated reward reinforcement pathways to psychosocial stressors, abuse of stimulants and psychopathology later in life.

Spasticity is evident in both humans and animals following spinal cord injury (SCI) and can contribute to significant functional limitation and disruption in quality of life of patients with this disorder. This mini-review describes a number of preclinical and clinical studies that promise to improve outcomes for, especially in terms of spasticity and hyper-reflexia, patients with SCI. A gold standard for the quantification of spasticity has proved elusive, but the combination of H-reflex frequency dependent depression and a novel stretch reflex (SR) windup protocol have the potential to provide new insights. As the pathophysiology of hyper-reflexia and spasticity continue to be investigated, the documented onset in the animal model of SCI provides critical time points for further study into these complex mechanisms. The positive effects of a passive exercise protocol and several potential pharmacological interventions are reviewed as well as a novel potential mechanism of action. Further work is needed to determine additional mechanisms that are involved in SCI, and how to optimize multiple therapies to overcome some of the deficits induced by SCI.

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 memory in TgCRND8 mice, in comparison to their own baseline before treatment. These results provide evidence that DBS could enhance short-term memory in a mouse model of AD by increasing synaptic transmission and α-secretase activity in the CA1 region of hippocampus.

It has been reported that individuals with autism spectrum disorder (ASD) have abnormal responses to the sensory environment. For these individuals sensory overload can impair functioning, raise physiological stress, and adversely affect social interaction. Early-stage (i.e. within 200 ms of stimulus onset) auditory processing abnormalities have been widely examined in ASD using event-related potentials (ERP), while ERP studies investigating early-stage visual processing in ASD are less frequent. We wanted to test the hypothesis of early-stage visual processing abnormalities in ASD by investigating ERPs elicited in a visual oddball task using illusory figures. Our results indicate that individuals with ASD have abnormally large cortical responses to task irrelevant stimuli over both parieto-occipital and frontal regions-of-interest (ROI) during early stages of visual processing compared to the control group. Furthermore, ASD patients showed signs of an overall disruption in stimulus discrimination, and had a significantly higher rate of motor response errors.