Bio

Professional Education


  • Doctor of Philosophy, Universitat Zurich (2017)
  • Master of Science, Universitat Zurich (2012)
  • Bachelor of Science, Universitat Zurich (2011)

Publications

All Publications


  • Contribution of early Alzheimer's disease-related pathophysiology to the development of acquired epilepsy EUROPEAN JOURNAL OF NEUROSCIENCE Gschwind, T., Lafourcade, C., Gfeller, T., Zaichuk, M., Rambousek, L., Knuesel, I., Fritschy, J. 2018; 47 (12): 1534?62

    Abstract

    Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticA? mice whether AD-like pathology renders neuronal networks more susceptible to the development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticA? mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticA? mice compared to wild-type littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibres and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble A? species by intracerebroventricular A?-specific antibody application mitigated the hyperexcitable phenotype of ArcticA? mice and prevented early SRS onset. Therefore, the development of seizures at early stages of AD is mediated primarily by A? species causing widespread changes in synaptic function.

    View details for DOI 10.1111/ejn.13983

    View details for Web of Science ID 000437112300010

    View details for PubMedID 29862588

  • Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia MOLECULAR PSYCHIATRY Notter, T., Coughlin, J. M., Gschwind, T., Weber-Stadlbauer, U., Wang, Y., Kassiou, M., Vernon, A. C., Benke, D., Pomper, M. G., Sawa, A., Meyer, U. 2018; 23 (2): 323?34

    Abstract

    Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18?kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls. Using an infection-mediated neurodevelopmental mouse model, we show that schizophrenia-relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels. On the other hand, TSPO was markedly upregulated in a mouse model of acute neurodegeneration and reactive gliosis, which was induced by intrahippocampal injection of kainic acid. In both models, the changes in TSPO levels were not restricted to microglia but emerged in various cell types, including microglia, astrocytes and vascular endothelial cells. Human PET imaging using the second-generation TSPO radiotracer [11C]DPA-713 revealed a strong trend towards reduced TSPO binding in the middle frontal gyrus of patients with recent-onset schizophrenia, who were previously shown to display increased levels of inflammatory cytokines in peripheral and central tissues. Together, our findings challenge the common assumption that central low-grade inflammation in schizophrenia is mirrored by increased TSPO expression or ligand binding. Our study further underscores the need to interpret altered TSPO binding in schizophrenia with caution, especially when measures of TSPO are not complemented with other markers of inflammation. Unless more selective microglial markers are available for PET imaging, quantification of cytokines and other inflammatory biomarkers, along with their molecular signaling pathways, may be more accurate in attempts to characterize inflammatory profiles in schizophrenia and other mental disorders that lack robust reactive gliosis.

    View details for DOI 10.1038/mp.2016.248

    View details for Web of Science ID 000423441700018

    View details for PubMedID 28093569

  • Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency MOLECULAR PSYCHIATRY Labouesse, M. A., Lassalle, O., Richetto, J., Iafrati, J., Weber-Stadlbauer, U., Notter, T., Gschwind, T., Pujadas, L., Soriano, E., Reichelt, A. C., Labouesse, C., Langhans, W., Chavis, P., Meyer, U. 2017; 22 (7): 961?71

    Abstract

    Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.

    View details for DOI 10.1038/mp.2016.193

    View details for Web of Science ID 000403911900004

    View details for PubMedID 27843148

  • Establishing a learned-helplessness effect paradigm in C57BL/6 mice: Behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se NEUROPHARMACOLOGY Pryce, C. R., Azzinnari, D., Sigrist, H., Gschwind, T., Lesch, K., Seifritz, E. 2012; 62 (1): 358?72

    Abstract

    Uncontrollability of major life events has been proposed to be central to depression onset and maintenance. The learned helplessness (LH) effect describes a deficit in terminating controllable aversive stimuli in individuals that experienced aversive stimuli as uncontrollable relative to individuals that experienced the same stimuli as controllable. The LH effect translates across species and therefore can provide an objective-valid readout in animal models of depression. Paradigms for a robust LH effect are established and currently applied in rat but there are few reports of prior and current study of the LH effect in mouse. This includes the C57BL/6 mouse, typically the strain of choice for application of molecular-genetic tools in pre-clinical depression research. The aims of this study were to develop a robust paradigm for the LH effect in BL/6 mice, provide evidence for underlying psychological processes, and study the effect of a depression-relevant genotype on the LH effect. The apparatus used for in/escapable electro-shock exposure and escape test was a two-way shuttle arena with continuous automated measurement of locomotion, compartment transfers, e-shock escapes, vertical activity and freezing. Brother-pairs of BL/6 mice were allocated to either escapable e-shocks (ES) or inescapable e-shocks (IS), with escape latencies of the ES brother used as e-shock durations for the IS brother. The standard two-way shuttle paradigm was modified: the central gate was replaced by a raised divider and e-shock escape required transfer to the distal part of the safe compartment. These refinements yielded reduced superstitious, pre-adaptive e-shock transfers in IS mice and thereby increased the LH effect. To obtain a robust LH effect in all brother pairs, pre-screening for minor between-brother ES differences was necessary and did not confound the LH effect. IS mice developed reduced motor responses to e-shock, consistent with a motivational deficit, and absence of a learning curve for escapes at escape test, consistent with a cognitive deficit. When a tone CS was used to predict e-shock, IS mice exhibited increased reactivity to the CS, consistent with hyper-emotionality. There was no ES-IS difference in pain sensitivity. Mice heterozygous knockout for the 5-HTT gene exhibited an increased LH effect relative to wildtype mice. This mouse model will allow for the detailed molecular study of the aetiology, psychology, neurobiology and neuropharmacology of uncontrollability of aversive stimuli, a potential major aetiological factor and state marker in depression. This article is part of a Special Issue entitled 'Anxiety and Depression'.

    View details for DOI 10.1016/j.neuropharm.2011.08.012

    View details for Web of Science ID 000296826800040

    View details for PubMedID 21864549

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