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A role for gephyrin phosphorylation in sexual dimorphism in the brain

English title A role for gephyrin phosphorylation in sexual dimorphism in the brain
Applicant Tyagarajan Shiva
Number 192522
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.06.2020 - 31.05.2023
Approved amount 525'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Neurology, Psychiatry

Keywords (4)

GABAergic inhibition; Autism ; hippocampus circuit ; Interneuron development

Lay Summary (German)

Lead
Mechanismus für geschlechtsdivergente Gehirnverbindungen und -funktionen
Lay summary

Obwohl Sexualdimorphismen im Gehirn in der Regel den zirkulierenden Steroidhormonen während kritischer Zeitfenster der Entwicklung zugeschrieben werden, sind die zugrundeliegenden molekularen Mechanismen nicht gut verstanden. In diesem Projekt wollen wir untersuchen, wie die Phosphorylierung eines multifunktionalen Proteins (Gephyrin) zur männlichen und weiblichen Hirnverbindung beiträgt. Wichtig ist, dass Phosphorylierungsdefekte in Gephyrin sich spezifisch auf einen Subtyp von neuronalen Zellen, nämlich GABAergen parvalbumin-positiven Interneuronen, in sexuell dimorpher Weise auswirken. Die Signalwege, die zu den Unterschieden zwischen Parvalbumin-Neuronen bei Männern und Frauen während der Schaltkreisbildung beitragen, werden ebenfalls untersucht. Bei männlichen Autismus-Patienten wurde über eine reduzierte Parvalbumin-Interneuron-Dichte berichtet, so dass die Untersuchung der molekularen Grundlage für eine solche geschlechtsspezifische Verzerrung der Suszeptibilität von großer klinischer Relevanz sein wird.  

 

Direct link to Lay Summary Last update: 01.04.2020

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
159867 Post-transcriptional and post-translational cellular signals organize gephyrin scaffolds to facilitate GABAergic synapse plasticity. 01.04.2015 Project funding

Abstract

Specialized subtypes of GABAergic interneurons provide synaptic inhibition to control principal neuron excitability and synchronization in the hippocampal formation. At postsynaptic sites, GABAA receptor pools are activated by GABA and control downstream neuronal function. It has emerged that scaffolding proteins at postsynaptic sites operate as “signalling hubs” to integrate diverse cellular signals and modulate receptor availability at synapses. Our own research has consistently demonstrated that gephyrin integrates signals in the form of post-translational modifications (PTMs) to modulate receptor availability as well as GABAergic synapse formation in an activity-dependent manner. In particular, we have reported that manipulating gephyrin phosphorylation at identified residues (S268 and S270) affects the amplitude and frequency of miniature GABAergic inhibitory currents in pyramidal neurons. Gephyrin is a substrate for diverse kinase pathways, and the functional impact of its phosphorylation in vivo remains largely unknown. We have evidence showing that gephyrin phosphorylation within Parvalbumin (PV) interneurons contributes to sex dimorphic connectivity with pyramidal cells. Although sexual dimorphisms in the brain usually are attributed to circulating steroid hormones during critical time windows of development, the underlying molecular mechanisms are elusive. We propose that estradiol action on PV interneurons causes differential phosphorylation of gephyrin at S268 and S270 in males and females, contributing to hypo-connectivity of PV interneurons specifically in male mice. To test this hypothesis in vivo, we have developed new mouse lines GephS268A/S270A and GphnS268A/S270Aflox/flox that express phospho-null gephyrin mutation either globally or in a cell-specific manner. The generation of GphnS268A/S270A / Ai9-tdT flex-stop-flex / Nkx2.1 Cre or GphnS268A/S270Aflox/flox / Nkx2.1 Cre mutant transgene lines will allow us to effectively analyze the developmental timing and mechanistic basis for sexual dimorphism that arises through blockade of gephyrin phosphorylation at S268 and S270. Therefore, we will test whether estradiol signaling influences gephyrin phosphorylation at S268 and S270, which then might impinge onto mTOR-triggered nuclear transcriptional programs in sex-dependent manner. Using a combination of in vivo and in vitro approaches we will dissect the molecular mechanisms underlying PV interneuron hypo-connectivity in GphnS268A/S270A male mice, as well as their functional consequences, for example on changes in gamma and theta oscillations in freely moving mutant mice. Given the gender-specific alterations in PV interneuron ratio seen in human in autism-spectrum disorder patients, we will assess in GphnS268A/S270A mice whether they recapitulate these pathological changes. In turn, we also test whether introducing gephyrin S268E/S270E phospho-mimetic mutations can rescue PV hypo-connectivity in another mouse model of Autism (Arid1b+/-). Together, our proposed study has immediate clinical relevance as susceptibility to neurological diseases exhibit stark sex differences, whose molecular basis remains an open question.
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