Autism Spectrum Disorders; neuropsychiatric disorders; parvalbumin; calcium-binding proteins; calcium homeostasis
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.
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.
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.
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.
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.
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.
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.
Filice Federica, Schwaller Beat (2017), Parvalbumin and autism: different causes, same effect?, in Oncotarget
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.
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.
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.
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.