Biology subjects

Fuhrmann, M.

Publications and source records attributed to Fuhrmann, M..

25 records · Page 2Linked to original sources

bioRxiv2020

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex (PFC). We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia, and shed light on the underlying cellular mechanisms.

neuroscience↗

bioRxiv2020

The diagonal band of broca continually regulates olfactory-mediated behaviors by modulating odor-evoked responses within the olfactory bulb

Sensory perception is modulated in a top-down fashion by higher brain regions to regulate the strength of its own input resulting in the adaptation of behavioral responses. In olfactory perception, the horizontal diagonal band of broca (HDB), embedded in the basal forebrain modulates olfactory information processing by recruiting olfactory bulb (OB) interneurons to shape excitatory OB output. Currently, little is known about how specific HDB to OB top-down signaling affects complex olfactory-mediated behaviors. Here we show that the olfactory bulb is strongly and differentially innervated by HDB projections. HDB-silencing via tetanus toxin light chain led to reduced odor-evoked Ca2+-responses in glomeruli of the OB, underscoring HDBs role in odor response modulation. Furthermore, selective, light-mediated silencing of HDB to OB afferents completely prevented olfactory-mediated habituation and discrimination behaviors. Notably, also social habituation and discrimination behaviors were affected. Mono-transsynaptic tracing studies indicated a robust HDB innervation from the paraventricular nucleus (PVN). Here we provide evidence for a novel tri-synaptic PVN-HDB-OB axis responsible for modulating these types of behavior. Thus, HDB to OB projections constitute a central top-down pathway for olfactory-mediated habituation and discrimination behaviors.

neuroscience↗

bioRxiv2020

Hippocampal hyperactivity in a rat model of Alzheimers disease

Neuronal network dysfunction is a hallmark of Alzheimers disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in a rat model of AD at an early disease stage at the beginning of extracellular amyloid beta (A{beta}) deposition. We established two-photon Ca2+-imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed changes in the passive properties and intrinsic excitability of CA1 pyramidal neurons. Furthermore, we observed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. Surprisingly, all parameters measured to quantify synaptic inhibition and excitation onto CA1 pyramidal neurons were intact suggesting a cell immanent deficit. Our data support the view that altered intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of disease progression.

neuroscience↗

bioRxiv2019

Label-free characterization of Amyloid-β-plaques and associated lipids in brain tissues using stimulated Raman scattering microscopy

The brains of patients with neurodegenerative diseases such as Alzheimers Disease (AD) often exhibit pathological alterations that involve abnormal aggregations of proteins and lipids. Here, we demonstrate that high-resolution, label-free, chemically-specific imaging using Stimulated Raman Scattering Microscopy (SRS) provides novel insights into the biophysical properties and biochemical composition of such pathological structures. In brain slices of a mouse model of AD, SRS reveals large numbers of Amyloid-{beta} plaques that commonly form a characteristic, three-dimensional core-shell structure, with a fibrillar proteinaceous core surrounded by a halo-like shell of lipid-rich deposits. SRS spectroscopic imaging allows for a clean, label-free visualization of the misfolded ({beta}-sheet) Amyloid-{beta} content in the plaque core. Surrounding lipid-rich deposits are found to contain comparatively high concentrations of membrane lipids (sphingomyelin, phosphatidylcholine), but lower levels of cholesterol than healthy white matter structures. Overall, the SRS spectra of plaque-associated lipids closely resemble those of nearby neurites, with the notable difference of a higher degree of lipid unsaturation compared to healthy brain structures. We hypothesize that plaque-associated lipid deposits may result from neuritic dystrophy associated with AD, and that the observed increased levels of unsaturation could help identify the kinds of pathological alterations taking place. Taken together, our results highlight the potential of Stimulated Raman Scattering microscopy to contribute to a deeper understanding of neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Microglia motility depends on neuronal activity andpromotes structural plasticity in the hippocampus

Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

neuroscience↗

bioRxiv2018

Restoring memory by optogenetic synchronization of hippocampal oscillations in an Alzheimer’s disease mouse model

Disrupted neural oscillations are a feature of Alzheimers disease (AD). We observed reduced frequency of theta oscillations in the hippocampal local field potential (LFP) in a mouse model of beta-amyloidosis. By restoring the temporal organization of theta oscillations using LFP-guided closed-loop optogenetic stimulation of parvalbumin-positive interneurons, we could rescue memory deficits of APP/PS1 mice in the novel object recognition test.

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bioRxiv2018

Memory trace superimposition impairs recall in a mouse model of AD

Learning and memory processes depend on the hippocampus and are impaired in Alzheimers disease (AD). Active neuronal ensembles form an engram by encoding information during learning. Their reactivation is required for memory recall. However, it remains unresolved whether the engram in CA1 principal neurons is impaired under AD-like conditions. We used two-photon in vivo imaging to visualize the expression of the immediate early gene c-fos within CA1 neurons during contextual fear conditioning and retrieval. Surprisingly, we identified engrams in wild-type mice and in the mouse model of AD indicating intact memory formation. However, under AD-like conditions engrams were superimposed by a high number of newly recruited fosGFP+ neurons during memory recall. This superimposition resembled the network configuration of wild-type mice exposed to a novel context. Artificial superimposition of the memory trace during recall in wild-type mice was sufficient to induce memory impairment. Thus, we propose superimposition of the CA1 memory trace as a mechanism for memory impairment in a mouse model of AD.\n\nHighlightsO_LIDecreased fosGFP expression in direct vicinity to amyloid-{beta} plaques\nC_LIO_LIIntact engram in CA1 of APP/PS1 mice\nC_LIO_LIImpurity of the retrieval network in CA1 is sufficient to impair memory recall\nC_LI\n\nPoll et al. present a novel mechanism for memory impairment in a mouse model of AD. The potential memory trace was found intact in the CA1 region of the hippocampus. However, excessive neuronal activity during retrieval, was superimposing the memory trace in a mouse model of AD.

neuroscience↗