摘要：Background
NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing.
NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of
NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying
NRXN1α
+/- and showed increased calcium transients in patient neurons.
Methods
In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying
NRXN1α
+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism.
Results
NRXN1α
+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (
GRIN1,
GRIN3B,
SLC17A6,
CACNG3,
CACNA1A,
SHANK1), which are likely to couple with the increased excitability in
NRXN1α
+/- cortical neurons.
Conclusions
Together with recent evidence of increased calcium transients, our results showed that human
NRXN1α
+/- isoform deletions altered neuronal excitability and non-synaptic function, and
NRXN1α
+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12868-021-00661-0.
