Project

Discipline

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

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

Active participation

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

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.