Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism

Rocco Pizzarelli,Enrico Cherubini

doi:10.3389/fncel.2013.00085

Abstract

Autism Spectrum Disorders (ASDs) comprise an heterogeneous group of neuro-developmental abnormalities, mainly of genetic origin, characterized by impaired social interactions, communications deficits, and stereotyped behaviors. In a small percentage of cases, ASDs have been found to be associated with single mutations in genes involved in synaptic function. One of these involves the postsynaptic cell adhesion molecule neuroligin (NL) 3. NLs interact with presynaptic neurexins (Nrxs) to ensure a correct cross talk between post and presynaptic specializations. Here, transgenic mice carrying the human R451C mutation of Nlgn3, were used to study GABAergic signaling in the hippocampus early in postnatal life. Whole cell recordings from CA3 pyramidal neurons in slices from NL3R451C knock-in mice revealed an enhanced frequency of Giant Depolarizing Potentials (GDPs), as compared to controls. This effect was probably dependent on an increased GABAergic drive to principal cells as demonstrated by the enhanced frequency of miniature GABAA-mediated (GPSCs), but not AMPA-mediated postsynaptic currents (EPSCs). Changes in frequency of mGPSCs were associated with an acceleration of their decay kinetics, in the absence of any change in unitary synaptic conductance or in the number of GABAA receptor channels, as assessed by peak scaled non-stationary fluctuation analysis. The enhanced GABAergic but not glutamatergic transmission early in postnatal life may change the excitatory/inhibitory balance known to play a key role in the construction and refinement of neuronal circuits during postnatal development. This may lead to behavioral deficits reminiscent of those observed in ASDs patients.

Highlights

Autism Spectrum Disorders (ASDs) comprise a heterogeneous group of pathological conditions characterized by impaired social interactions, deficits in verbal and non verbal communication, limited interest in the surrounding environment associated with stereotyped and repetitive behavior (American Psychiatric Association, 2000)
Transgenic mice carrying the human R451C mutation of Nlgn3, were used to study GABAergic signaling in the hippocampus early in postnatal life
As ASDs are neurodevelopmental disorders, we first verified whether the NL3R451C mutation alters correlated network activity, the so-called Giant Depolarizing Potentials (GDPs), a hallmark of developmental networks (Ben-Ari et al, 1989, 2007)

Summary

Introduction

Autism Spectrum Disorders (ASDs) comprise a heterogeneous group of pathological conditions characterized by impaired social interactions, deficits in verbal and non verbal communication, limited interest in the surrounding environment associated with stereotyped and repetitive behavior (American Psychiatric Association, 2000). A small percentage of cases with idiopathic ASDs have been found to be associated with single mutations in genes involved in synapses organization, pointing to synaptic dysfunction as one possible cause of autism (Südhof, 2008). Mutations of genes encoding for cell adhesion molecules of the neuroligin (NL; Jamain et al, 2003; Laumonnier et al, 2004; Yan et al, 2005), neurexin (Nrx; Kim et al, 2008) families or for SHANK3, a scaffold protein involved in the structural organization of dendritic spines and a binding partner of NLs (Durand et al, 2007), have received particular attention. The bidirectional signaling through the NL-Nrx is crucial for synapse development and stabilization (Scheiffele et al, 2000; Varoqueaux et al, 2006; Chubykin et al, 2007; Ko et al, 2009; Poulopoulus et al, 2009)

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Conclusion