Proper Layering Is Important for Precisely Timed Activation of Hippocampal Mossy Cells

The mammalian cortex exhibits a laminated structure that may underlie optimal synaptic connectivity and support temporally precise activation of neurons. In ‘reeler' mice, the lack of the extracellular matrix protein Reelin leads to abnormal positioning of cortical neurons and disrupted layering. To address how these structural changes impact neuronal function, we combined electrophysiological and neuroanatomical techniques to investigate the synaptic activation of hippocampal mossy cells (MCs), the cell type that integrates the output of dentate gyrus granule cells (GCs). While somatodendritic domains of wild-type (WT) MCs were confined to the hilus, the somata and dendrites of reeler MCs were often found in the molecular layer, where the perforant path (PP) terminates. Most reeler MCs received aberrant monosynaptic excitatory input from the PP, whereas the disynaptic input to MCs via GCs was decreased and inhibition was increased. In contrast to the uniform disynaptic discharge of WT MCs, many reeler cells discharged with short, monosynaptic latencies, while others fired with long latencies over a broad temporal window in response to PP activation. Thus, disturbed lamination results in aberrant synaptic connectivity and altered timing of action potential generation. These results highlight the importance of a layered cortical structure for information processin

Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice

Microglia are suggested to be involved in several neuropsychiatric diseases. Indeed changes in microglia morphology have been reported in different mouse models of depression. A crucial regulatory system for microglia function is the well-defined CX3C axis. Thus, we aimed to clarify the role of microglia and CX3CR1 in depressive behavior by subjecting CX3CR1-deficient mice to a particular chronic despair model (CDM) paradigm known to exhibit face validity to major depressive disorder. In wild-type mice we observed the development of chronic depressive-like behavior after 5 days of repetitive swim stress. 3D-reconstructions of Iba-1-labeled microglia in the dentate molecular layer revealed that behavioral effects were associated with changes in microglia morphology towards a state of hyper-ramification. Chronic treatment with the anti-depressant venlafaxine ameliorated depression-like behavior and restored microglia morphology. In contrast, CX3CR1 deficient mice showed a clear resistance to either (i) stress-induced depressive-like behavior, (ii) changes in microglia morphology and (iii) antidepressant treatment. Our data point towards a role of hyper-ramified microglia in the etiology of chronic depression. The lack of effects in CX3CR1 deficient mice suggests that microglia hyper-ramification is controlled by neuron-microglia signaling via the CX3C axis. However, it remains to be elucidated how hyper-ramified microglia contribute to depressive-like behavior. (C) 2015 Elsevier Inc. All rights reserved

Cardiovascular and renal disease in the adolescent guinea pig after chronic placental insufficiency

OBJECTIVE:The aim of this study was to determine the long-term effects of chronic placental insufficiency on the metabolic state and organ structure in the fetal and adolescent guinea pig. STUDY DESIGN: The maternal uterine artery was ligated at day 28–30 to reduce placental function and restrict fetal growth. Whole body and tissue weights and plasma metabolites were determined at 60 days of gestation and 8 weeks of age; tissue structure was determined at the latter age in restricted and control offspring. RESULTS: Fetal growth restriction increased fibrosis in the heart and kidneys (P < .05), increased aortic wall thickening (P < .01), reduced the number of glomeruli in the kidneys (P < .05), and increased the plasma urea and chloride in adolescent offspring. CONCLUSION: This study demonstrates that diseases in the heart, aorta, and kidneys that result from an adverse prenatal environment are evident at adolescence and may contribute to subsequent adult disease.Todd A. Briscoe, Alexandra E. Rehn, Sandra Dieni, Jhodie R. Duncan, Mary E. Wlodek, Julie A. Owens and Sandra M. Ree

BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons

Although brain-derived neurotrophic factor (BDNF) regulates numerous and complex biological processes including memory retention, its extremely low levels in the mature central nervous system have greatly complicated attempts to reliably localize it. Using rigorous specificity controls, we found that antibodies reacting either with BDNF or its pro-peptide both stained large dense core vesicles in excitatory presynaptic terminals of the adult mouse hippocampus. Both moieties were ?10-fold more abundant than pro-BDNF. The lack of postsynaptic localization was confirmed in Bassoon mutants, a seizure-prone mouse line exhibiting markedly elevated levels of BDNF. These findings challenge previous conclusions based on work with cultured neurons, which suggested activity-dependent dendritic synthesis and release of BDNF. They instead provide an ultrastructural basis for an anterograde mode of action of BDNF, contrasting with the long-established retrograde model derived from experiments with nerve growth factor in the peripheral nervous system

Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model

Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] a-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). a-synuclein transgenic mice with short telomeres (aSYN(tg/tg) G3Terc(-/-)) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of a-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in aSYN(tg/tg) G3Terc(-/-) microglia animals. These results provide the first experimental data that telomere shortening accelerates a-synuclein pathology that is linked to limited microglia function in the brainstem