Albrecht Kunze

Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus

In the adult dentate gyrus, radial glia-like cells represent putative stem cells generating neurons and glial cells. Here, we combined patch-clamp recordings, biocytin filling, immunohistochemistry, single-cell transcript analysis, and mouse transgenics to test for connexin expression and gap junctional coupling of radial glia-like cells and its impact on neurogenesis. Radial glia-like cells were identified in mice expressing EGFP under control of the nestin and gfap promoters. We show that a majority of Radial glia-like cells are coupled and express Cx43. Neuronal precursors were not coupled. Mice lacking Cx30 and Cx43 in GFAP-positive cells displayed almost complete inhibition of proliferation and a significant decline in numbers of radial glia-like cells and granule neurons. Inducible virus-mediated ablation of connexins in the adult hippocampus also reduced neurogenesis. These findings strongly suggest the requirement of connexin expression by radial glia-like cells for intact neurogenesis in the adult brain and point to possible communication pathways of these cells.

Rehabilitative therapies differentially alter proliferation and survival of glial cell populations in the perilesional zone of cortical infarcts.

Rehabilitative therapies after stroke are designed to improve remodeling of neuronal circuits and to promote functional recovery. Only very little is known about the underlying cellular mechanisms. In particular, the effects of rehabilitative training on glial cells, which play an important role in the pathophysiology of cerebral ischemia, are only poorly understood. Here, we examined the effects of rehabilitative therapies on proliferation and survival of distinct glial populations in the perilesional area of photochemically induced focal ischemic infarcts in the forelimb sensorimotor cortex in rats. Immediately after the infarct, one group of animals housed in standard cages received daily sessions of skilled reaching training of the impaired forelimb; a second group was transferred to an enriched environment, whereas a third control group remained in standard cages without further treatment. Functional recovery was assessed in a sensorimotor walking task. To label proliferating cells, bromodeoxyuridine (BrdU) was administered from day 2 until day 6 postinfarct. Proliferation and survival of astrocytes, microglia/macrophages, and immature and mature oligodendrocytes in the perilesional zone were immunocytochemically quantified at day 10 and 42. Using this approach, we demonstrate that enriched environment and reaching training both significantly improve functional recovery of the impaired forelimb. Furthermore, these therapies strongly reduce the proliferation of microglia/macrophages in the perilesional zone, and daily training of the impaired forelimb significantly increased the survival of newly generated astrocytes. Our data, therefore, demonstrate that rehabilitative therapies after cortical infarcts not only improve the functional recovery but also significantly influence the glial response in the perilesional zone.

Proliferative response of distinct hippocampal progenitor cell populations after cortical infarcts in the adult brain.

Precursor cells in the adult dentate gyrus are a heterogeneous population. Astrocytic cell types with radial glia-like morphology and low proliferative activity have been distinguished from highly dividing subtypes expressing early neuronal properties. Recent evidence indicates that physiological stimuli predominantly increased proliferation of non-astrocytic cell types whereas radial glia-like precursors remained quiescent. We here analyzed the proliferative response of precursor cell subtypes under pathophysiological conditions in a model of photochemical cortical infarcts. Using transgenic pNestin-GFP mice and single intraperitoneal injections of 5-bromo-2-deoxyuridine 4 h after surgery, immunocytochemical analysis revealed a differential activation of the distinct subpopulations within 72 h after the infarct. The stimulation was most prominent in radial glia-like precursor cells but also non-astrocytic precursors with early neuronal phenotypes were activated. The present study indicates that the proliferative response of precursor cell subpopulations in the subgranular zone might differ under physiological and pathophysiological conditions.

Two distinct populations of doublecortin-positive cells in the perilesional zone of cortical infarcts

BackgroundRecovery following stroke depends on cellular plasticity in the perilesional zone (PZ). Doublecortin (DCX), a protein mainly labeling immature neurons in neurogenic niches is also highly expressed in the vicinity of focal cortical infarcts. Notably, the number of DCX+ cells positively correlates with the recovery of functional deficits after stroke though the nature and origin of these cells remains unclear.ResultsIn the present study, we aimed to characterize the population of DCX+ cells in the vicinity of ischemic infarcts in a mouse model in detail. Employing a photothrombosis model, distinct immunohistochemical techniques, stereology and confocal microscopy, we show that: i) DCX+ cells in the perilesional zone do not constitute a homogenous population and two cell types, stellate and polar cells can be distinguished according to their morphology. ii) Stellate cells are mainly located in the lateral and medial vicinity of the insult and express astrocytic markers. iii) Polar cells are found almost exclusively in the corpus callosum region including in the preserved deep cortical layers close to the subventricular zone (SVZ). Further, they do not show any colocalisation of glial markers. Polar morphology and distribution suggest a migration towards the lesion.ConclusionsIn summary, our findings provide evidence that in mice DCX+ cells in the perilesional zone of cortical infarcts comprise a distinct cell population and the majority of cells are of glial nature.

Serial FDG PET/CT in autoimmune encephalitis with faciobrachial dystonic seizures.

Autoimmune encephalitis (AE) is increasingly recognized as a nonparaneoplastic disorder with autoantibodies to neuronal proteins. Although MRI is frequently unremarkable, PET imaging might contribute to identification of affected brain regions in distinct AE. We report on serial FDG PET in a 72-year-old man with particular AE subtype, with potassium channel complex antibodies and prodromal stage with dystonic seizures. Serial FDG PET/CT revealed that besides limbic structures, basal ganglia are centrally involved and presumably play a key role in the generation of dystonic seizures.

Adult hippocampal neurogenesis poststroke: More new granule cells but aberrant morphology and impaired spatial memory

Stroke significantly stimulates neurogenesis in the adult dentate gyrus, though the functional role of this postlesional response is mostly unclear. Recent findings suggest that newborn neurons generated in the context of stroke may fail to correctly integrate into pre-existing networks. We hypothesized that increased neurogenesis in the dentate gyrus following stroke is associated with aberrant neurogenesis and impairment of hippocampus-dependent memory. To address these questions we used the middle cerebral artery occlusion model (MCAO) in mice. Animals were housed either under standard conditions or with free access to running wheels. Newborn granule cells were labelled with the thymidine analoque EdU and retroviral vectors. To assess memory performance, we employed a modified version of the Morris water maze (MWM) allowing differentiation between hippocampus dependent and independent learning strategies. Newborn neurons were morphologically analyzed using confocal microscopy and Neurolucida system at 7 weeks. We found that neurogenesis was significantly increased following MCAO. Animals with MCAO needed more time to localize the platform and employed less hippocampus-dependent search strategies in MWM versus controls. Confocal studies revealed an aberrant cell morphology with basal dendrites and an ectopic location (e.g. hilus) of new granule cells born in the ischemic brain. Running increased the number of new neurons but also enhanced aberrant neurogenesis. Running, did not improve the general performance in the MWM but slightly promoted the application of precise spatial search strategies. In conclusion, ischemic insults cause hippocampal-dependent memory deficits which are associated with aberrant neurogenesis in the dentate gyrus indicating ischemia-induced maladaptive plasticity in the hippocampus.

Familiäre Alzheimer-Variante mit Amyloidangiopathie als Ausdruck einer APP-Gen-Duplikation@@@Hereditary Alzheimer’s disease with amyloid angiopathy caused by amyloid precursor protein locus

We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimers disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimers dementia. The co-occurrence of CSF changes typical for Alzheimers disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis.

[Hereditary Alzheimer's disease with amyloid angiopathy caused by amyloid precursor protein locus].

We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimers disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimers dementia. The co-occurrence of CSF changes typical for Alzheimers disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis.

Familiäre Alzheimer-Variante mit Amyloidangiopathie als Ausdruck einer APP-Gen-Duplikation

We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimers disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimers dementia. The co-occurrence of CSF changes typical for Alzheimers disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis.