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Parvalbumin deficiency - a common endpoint mouse model for Autism Spectrum Disorders?

English title Parvalbumin deficiency - a common endpoint mouse model for Autism Spectrum Disorders?
Applicant Schwaller Beat
Number 155952
Funding scheme Project funding (Div. I-III)
Research institution OMI Medicine University of Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2015 - 30.06.2018
Approved amount 550'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (5)

Autism Spectrum Disorders; neuropsychiatric disorders; parvalbumin; calcium-binding proteins; calcium homeostasis

Lay Summary (German)

Lead
Intrazelluläre Kalziumsignale spielen eine wichtige Rolle bei vielen biologischen Vorgängen, so auch bei der Kommunikation zwischen Nervenzellen. Zu diesem Zweck haben Neurone komplexe Proteinmoleküle entwickelt, welche Kalziumsignale präzise regulieren. So ist es nicht erstaunlich, dass Störungen in diesen Signalwegen mit neuropsychiatrischen Erkrankungen wie z. Bsp. Autismus, bipolaren Störungen oder Schizophrenie in Zusammenhang gebracht wurden. Im Falle von Autismus deutet einiges darauf hin, dass eine Störung von Kalziumsignalwegen eine Rolle bei dieser Krankheit spielen könnte. Funktionelle Störungen in einer kleinen Untergruppe von inhibitorischen Neuronen, die das kalzium-bindende Protein Parvalbumin produzieren, könnten wichtig für die Manifestation des Autismus-Phänotyps sein. Aenderungen in der Funktionsweise dieser Neurone infolge von Genveränderungen deuten darauf hin, dass diese mit grosser Wahrscheinlichkeit zum Krankheitsbild des Autismus beitragen.
Lay summary

Im Forschungsprojekt soll untersucht werden, inwiefern Veränderungen in der Konzentration von Parvalbumin, welches normalerweise als Marker für diese Neuronen-Subpopulation dient, eine Rolle beim Autismus-Phänotypen spielen könnte. Dazu werden Mausmodelle verwendet, bei denen die Parvalbumin-Expression gezielt gesteuert werden kann oder bei denen das Protein aufgrund einer Genmanipulation fehlt, bei sogenannten Knockout-Mäusen. In den Parvalbumin-Knockout-Mäusen soll mit verschiedensten Methoden, von der Elektrophysiolgie bis zum Verhalten, untersucht werden, wie das Fehlen dieses Proteins die Funktionsweise des Hirns und damit das Verhalten der Mäuse verändert. Im weitern wird untersucht, ob auch in anderen genetischen Maus-Autismusmodellen die Konzentration oder die Verteilung von Parvalbumin verändert ist. 

 

Direct link to Lay Summary Last update: 17.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes
Janickova Lucia, Rechberger Karin Farah, Wey Lucas, Schwaller Beat (2020), Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes, in Molecular Autism, 11(1), 47-47.
Amyloid pathology‐produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites
Angulo Sergio L., Henzi Thomas, Neymotin Samuel A., Suarez Manuel D., Lytton William W., Schwaller Beat, Moreno Herman (2020), Amyloid pathology‐produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites, in Alzheimer's & Dementia, 16(2), 251-261.
Parvalbumin expression in oligodendrocyte-like CG4 cells causes a reduction in mitochondrial volume, attenuation in reactive oxygen species production and a decrease in cell processes’ length and branching
Lichvarova Lucia, Blum Walter, Schwaller Beat, Szabolcsi Viktoria (2019), Parvalbumin expression in oligodendrocyte-like CG4 cells causes a reduction in mitochondrial volume, attenuation in reactive oxygen species production and a decrease in cell processes’ length and branching, in Scientific Reports, 9(1), 10603-10603.
Inducible and reversible silencing of the Pvalb gene in mice: An in vitro and in vivo study
Filice Federica, Blum Walter, Lauber Emanuel, Schwaller Beat (2019), Inducible and reversible silencing of the Pvalb gene in mice: An in vitro and in vivo study, in European Journal of Neuroscience, 50(4), 2694-2706.
Dysregulation of Parvalbumin Expression in the Cntnap2-/- Mouse Model of Autism Spectrum Disorder
Lauber Emanuel, Filice Federica, Schwaller Beat (2018), Dysregulation of Parvalbumin Expression in the Cntnap2-/- Mouse Model of Autism Spectrum Disorder, in Frontiers in molecular neuroscience, 11, 262-262.
17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms
Filice Federica, Lauber Emanuel, Vörckel Karl Jakob, Wöhr Markus, Schwaller Beat (2018), 17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms, in Molecular Autism, 9(1), 15-15.
Parvalbumin neurons as a hub in autism spectrum disorders.
Lauber Emanuel, Filice Federica, Schwaller Beat (2018), Parvalbumin neurons as a hub in autism spectrum disorders., in Journal of neuroscience research, 96(3), 360-361.
Parvalbumin and autism: different causes, same effect?
Filice Federica, Schwaller Beat (2017), Parvalbumin and autism: different causes, same effect?, in Oncotarget, 7222-7223.
Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice
Lauber Emanuel, Filice Federica, Schwaller Beat (2016), Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice, in Frontiers in Molecular Neuroscience, 9, 1-16.
Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism.
Filice Federica, Vörckel Karl Jakob, Sungur Ayse Özge, Wöhr Markus, Schwaller Beat (2016), Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism., in Molecular brain, 9(1), 10-10.
Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities
Wöhr M, Orduz D, Gregory P, Moreno H, Khan U, Vörckel K J, Wolfer D P, Welzl H, Gall D, Schiffmann S N, Schwaller B (2015), Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities, in Translational Psychiatry, 5(3), e525-e525.

Collaboration

Group / person Country
Types of collaboration
M. Wöhr, Universität Marburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
D. Wolfer, ETHZ-UniZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
ma thèse in 180'' Performances, exhibitions (e.g. for education institutions) 18.05.2017 Université de Genève, Switzerland Filice Federica;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television ma thèse en 180'' RTS Western Switzerland 2017

Associated projects

Number Title Start Funding scheme
184668 Parvalbumin deficiency - a point of convergence in Autism Spectrum Disorders and schizophrenia? 01.06.2019 Project funding (Div. I-III)
130680 Knock-out mice for the calcium-binding proteins parvalbumin, calbindin D-28k and calretinin. Models for muscle and brain diseases. 01.05.2010 Project funding (Div. I-III)
147697 From asbestos-exposure to cancer: a systemic approach to detect loss of homeostatic control in the mesothelial environment 01.08.2013 Sinergia

Abstract

Intracellular Ca2+ signals are highly complex in space and time and in neurons they control many cellular processes. At short time scales, they govern transmitter release and associated short-term plasticity, at longer time scales, the precise spatiotemporal aspects of Ca2+ signals also regulate Ca2+-dependent excitation-transcription (E-T) coupling. The latter is implicated in modifying molecules in pre- and post-synaptic compartments, also leading to morphological alterations of synapses, finally affecting cognition, learning and memory. In order to achieve the necessary precision in Ca2+ signaling, each neuron is equipped with a specific sophisticated machinery, the “Ca2+ signaling toolkit” that comprises Ca2+ channels and pumps, proteins involved in organellar Ca2+ handling (ER, mitochondria) as well as Ca2+ buffers. Given the complexity of neuronal Ca2+ signals, it is not astonishing that malfunctioning of Ca2+-regulated processes is causing or linked with neuropsychiatric disorders such as autism spectrum disorders (ASD), schizophrenia and bipolar disorder. ASD comprise a group of related neurodevelopmental disorders with a strong genetic component, but phenotypic and genetic heterogeneity; approximately 1 in 100 children displays symptoms or mild signs related to ASD. The etiology of ASD remains unclear, but the most discussed hypotheses include defects in synapse formation/structure/maintenance or alterations in signaling pathways relying the information from the synapse to the nucleus (including alterations in Ca2+ signaling), finally leading to an excitation/inhibition (E/I) imbalance. A computational systems biology approach resulting in an integrative gene/environment interactions network found the Ca2+ node to be the most relevant one for ASD. A gaze from the viewpoint of neurons and neuronal networks suggests the dysfunction of interneurons and more precisely the subpopulation of interneurons expressing the Ca2+-binding protein parvalbumin (PV) to play a major role in psychiatric disorders including ASD and schizophrenia. The PV+ interneurons are part of the ˜ 10 - 15% GABAergic cortical neurons and are critically involved in maintaining the E/I balance and are essential for controlling brain rhythms implicated in cognition and information processing. A decrease in the “number of PV+ neurons” is observed in patients with schizophrenia and ASD, as well as in genetic ASD mouse models. Thus, the reputed Ca2+ buffer PV is placed exactly at the intersection of altered Ca2+ signaling and dysfunction of PV+ interneurons in ASD. With the help of transgenic mouse models including PV null-mutant (PV-/-) mice, the Schwaller lab has extensively investigated the role of PV in various types of PV+ neurons and we found the absence of PV to result in alterations in modulation of short-term plasticity, neuron excitability and gamma rhythms in vitro. PV’s absence in vivo affects firing properties of PV+ neurons and facilitates synchronous activity in the cortex. An initial behavioral analysis of PV-/- mice revealed these mice to show an ASD-like phenotype including the triad of core symptoms: reduced social interactions, impaired communication skills and restricted and stereotyped behavior.Here we propose first to carry out an in-depth characterization of PV-/- and PV+/- mice at different levels (e.g. brain morphology, behavior) to validate, whether they represent bona fide endpoint models for ASD and/or schizophrenia. Moreover, we need to ascertain that the phenotype caused by PV’s absence/reduction is the result of the absence/reduction of PV protein and not the consequence of a partial loss of PV+ neurons. Unbiased stereological methods are used to quantify the number of “PV+ neurons” using specific PV+-interneuron markers including VVA that binds to perineuronal nets surrounding these neurons. Furthermore, we will investigate in validated genetic and environmental ASD mouse models (mice mutant for Shank 1 or 3 or PolyI:C treatment, respectively), whether the previously reported “decrease in the number of PV+ neurons” is the result of a decrease in PV expression and/or a loss of PV+ neurons. Most importantly and as a proof-of-concept, we will re-express and/or up-regulate PV by genetic and/or pharmacological approaches in PV-reduced (PV+/- and PV-/-) and in other ASD mouse models with the aim to rescue the WT behavioral phenotype. For the first time, we expect to establish a robust “common endpoint” ASD model based on PV down-regulation that might I) provide a common link between the many apparently unrelated ASD-associated synapse structure/function and/or E/I imbalance phenotypes and II) be used also for drug testing possibly leading to novel therapeutic treatments. PV down-regulation might represent one of the points of convergence in ASD.
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