Radyushkin K.,Max Planck Institute for Experimental Medicine |
Radyushkin K.,Center for Molecular Physiology of the Brain |
El-Kordi A.,Max Planck Institute for Experimental Medicine |
El-Kordi A.,Center for Molecular Physiology of the Brain |
And 12 more authors.
Genes, Brain and Behavior | Year: 2010
Schizophrenia is a devastating disease that affects approximately 1% of the population across cultures. Its neurobiological underpinnings are still unknown. Accordingly, animal models of schizophrenia often lack construct validity. As concordance rate in monozygotic twins amounts to only 50%, environmental risk factors (e.g. neurotrauma, drug abuse, psychotrauma) likely act as necessary 'second hit' to trigger/drive the disease process in a genetically predisposed individual. Valid animal models would have to consider this genetic-environmental interaction. Based on this concept, we designed an experimental approach for modeling a schizophrenia-like phenotype in mice. As dysfunction in synaptic transmission plays a key role in schizophrenia, and complexin2 (CPLX2) gene expression is reduced in hippocampus of schizophrenic patients, we developed a mouse model with Cplx2 null mutation as genetic risk factor and a mild parietal neurotrauma, applied during puberty, as environmental 'second hit'. Several months after lesion, Cplx2 null mutants showed reduced pre-pulse inhibition, deficit of spatial learning and loss of inhibition after MK-801 challenge. These abnormalities were largely absent in lesioned wild-type mice and non-lesioned Cplx2 null mutants. Forced alternation in T-maze, object recognition, social interaction and elevated plus maze tests were unaltered in all groups. The previously reported mild motor phenotype of Cplx2 null mutants was accentuated upon lesion. MRI volumetrical analysis showed a decrease of hippocampal volume exclusively in lesioned Cplx2 null mutants. These findings provide suggestive evidence for the 'second hit' hypothesis of schizophrenia and may offer new tools for the development of advanced treatment strategies. © 2010 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society.
Kittelmann M.,European Neuroscience Institute |
Kittelmann M.,Schwann Schleiden Center for Molecular Cell Biology |
Hegermann J.,European Neuroscience Institute |
Hegermann J.,Center for Molecular Physiology of the Brain |
And 10 more authors.
Journal of Cell Biology | Year: 2013
Synaptic vesicle (SV) release is spatially and temporally regulated by a network of proteins that form the presynaptic active zone (AZ). The hallmark of most AZs is an electron-dense projection (DP) surrounded by SVs. Despite their importance for our understanding of triggered SV release, high-resolution analyses of DP structures are limited. Using electron microscopy, we show that DPs at Caenorhabditis elegans neuromuscular junctions (NMJs) were highly structured, composed of building units forming bays in which SVs are docked to the AZ membrane. Furthermore, larger ribbonlike DPs that were multimers of the NMJ building unit are found at synapses between inter- and motoneurons. We also demonstrate that DP size is determined by the activity of the AZ protein SYD-2/Liprin-α. Whereas loss of syd-2 function led to smaller DPs, syd-2 gain-of-function mutants displayed larger ribbonlike DPs through increased recruitment of ELKS-1/ ELKS. Therefore, our data suggest that a main role of SYD-2/ Liprin-α in synaptogenesis is to regulate the polymerization of DPs. © 2013 Kittelmann et al.
Griesel G.,Max Planck Institute for Biophysical Chemistry |
Krug C.,Max Planck Institute for Biophysical Chemistry |
Yurlova L.,Max Planck Institute for Biophysical Chemistry |
Diaconu M.,Max Planck Institute for Biophysical Chemistry |
And 3 more authors.
Gene Expression Patterns | Year: 2011
Lmx1a is a member of the LIM homeodomain containing transcription factors and plays an important role during embryonic development. Specifically, it is required for the proper formation of several structures in the central nervous system, such as the roof plate, the cerebellum, and the inner ear. All these defects may contribute to the neurological phenotype observed in dreher mice, lacking functional Lmx1a protein. Interestingly, this factor was also found to promote midbrain dopaminergic neuron fate. We have introduced Green fluorescent protein (GFP) coding sequences into the Lmx1a locus by homologous recombination, and created knockout mice where GFP recapitulates the Lmx1a endogenous expression pattern. © 2011 Elsevier B.V. All rights reserved.
Wedekind D.,University of Gottingen |
Neumann K.,University of Gottingen |
Falkai P.,University of Gottingen |
Falkai P.,Center for Molecular Physiology of the Brain |
And 5 more authors.
European Archives of Psychiatry and Clinical Neuroscience | Year: 2011
Elevations of serum homocysteine levels are a consistent finding in alcohol addiction. Serum S100B levels are altered in different neuropsychiatric disorders but not well investigated in alcohol withdrawal syndromes. Because of the close connection of S100B to ACTH and glutamate secretion that both are involved in neurodegeneration and symptoms of alcoholism the relationship of S100B and homocysteine to acute withdrawal variables has been examined. A total of 22 male and 9 female inpatients (mean age 46.9 ± 9.7 years) with an ICD-10 diagnosis of alcohol addiction without relevant affective comorbidity were examined on admission and after 24, 48, and 120 h during withdrawal. S100B and homocysteine levels in serum were collected, and severity of withdrawal symptoms (AWS-scale), applied withdrawal medication, initial serum ethanol levels and duration of addiction were recorded. Serum S100B and homocysteine levels declined significantly (P < .05) over time. Both levels declined with withdrawal syndrome severity. Females showed a trend to a more intense decline in serum S100B levels compared to males at day 5 (P = .06). Homocysteine levels displayed a negative relationship to applied amount of clomethiazole (P < .05) and correlated with age of onset of addiction. No withdrawal seizures were recorded during the trial. As it is known for homocysteine, S100B revealed to decline rapidly over withdrawal treatment in alcoholism. This effect is more pronounced in female patients. S100B could be of relevance in the neurobiology of alcohol withdrawal syndromes. It may be indirectly related to the level of stress level or glutamatergic activity during alcohol withdrawal. © 2010 The Author(s).
Novikova O.,RAS Institute of Cytology and Genetics |
Papusheva E.,Hannover Medical School |
Ponimaskin E.,Hannover Medical School |
Ponimaskin E.,Center for Molecular Physiology of the Brain |
Blinov A.,RAS Institute of Cytology and Genetics
Russian Journal of Genetics | Year: 2011
Non-Long Terminal Repeats (non-LTR or LINE) retrotransposons belong to the class of mobile genetic elements that are transposed into the host genome by reverse transcription of the RNA intermediate. Most of non-LTR retrotransposons contain two open reading frames (ORFs). The ORF1 codes for a gag-like protein, while the ORF2 codes for a reverse transcriptase (RT). We cloned two constructs based on Jockey-like non-LTR retrotransposon from genome Chironomus thummi (NLR1Cth). The retroposition assay performed in Chinese hamster ovary (CHO) cells demonstrated genome integrations of both constructs. The finding that the insect mobile element NLR1Cth is functional in mammalian cells demonstrates that this element possess universal enzymatic machinery allowing for active propagation in the genome of distant taxa. This suggests that the NLR1Cth transposon system may represent a useful tool for genetic analysis and manipulation in vertebrate cells. © 2011 Pleiades Publishing, Ltd.