Abstract
Given its high penetrance, clearly delineated and evolutionary conserved genomic structure, mouse models of the 22q11.2 deletion provide an ideal organism-based and cell-based model of this well-established disease mutation for schizophrenia. In this study we examined the development of changes in intrinsic properties, action potential firing and synaptic transmission using whole-cell patch-clamp recordings of cultured embryonic cortical neurons from Df(16)A+/− and WT mice at DIV7 and DIV14, respectively. Compared to neurons from the WT littermates, significantly increased input resistance and decreased rising rate of action potential was observed in Df(16)A+/− mice at DIV7 but not at DIV14 indicative of delayed neuronal maturation. Neurons from Df(16)A+/− mice also showed significantly higher cellular excitability at both DIV7 and DIV14. Evaluation of Ca2+ homeostasis perturbation caused by 22q11.2 deletion using calcium imaging revealed a significantly lower amplitude of calcium elevation and a smaller area under the curve after depolarization in neurons from Df(16)A+/− mice at both DIV7 and DIV14. Furthermore, the properties of inhibitory synaptic events were significantly altered in Df(16)A+/− mice. We identified changes in mRNA expression profiles, especially in ion channels, receptors, and transporters that may underlie the neurophysiological effects of this mutation. Overall, we show a number of alterations in electrophysiological and calcium homeostatic properties of embryonic cortical neurons from a 22q11.2 deletion mouse model at different culture times and provide valuable insights towards revealing disease mechanisms and discovery of new therapeutic compounds.
Highlights
While much progress has been made recently in understanding the genetic causes of psychiatric illnesses, there remain many unresolved questions pertaining to the underlying neural mechanisms. 22q11.2 deletions represent one of the greatest known genetic risk factors for schizophrenia (SCZ)
Using the Df(16)A+/− mouse strain we investigated the physiological properties of cultured embryonic cortical neurons from mutant and wild-type (WT) mice at two different time points (DIV7 and DIV14) and explored how the deletion affects the membrane properties, firing patterns, and synaptic activity during neural development and maturation in vitro
A significant change of resting membrane potential (RMP) was observed in Df(16)A+/− cortical neurons from –51.96 ± 2.16 mV (n = 28) at DIV7 to –57.92 ± 1.04 mV (n = 26) at DIV14 (t test, p < 0.05, Fig. 1b)
Summary
While much progress has been made recently in understanding the genetic causes of psychiatric illnesses, there remain many unresolved questions pertaining to the underlying neural mechanisms. 22q11.2 deletions represent one of the greatest known genetic risk factors for schizophrenia (SCZ). Sun et al Translational Psychiatry (2018)8:85 and the age of the mice tested, taken together, previous studies on this mouse model revealed robust alterations of electrophysiological properties, synaptic function and plasticity, dopaminergic and GABAergic neuromodulation as well as structural and functional neuronal connectivity both within and between brain areas, in hippocampus and prefrontal cortex[9,10,11,13,14,16,17] These effects are in part due to chromosomal deficiency induced disruptions in microRNA processing and protein palmitoylation[7,8,18], the impact of these and other processes affected by this genomic lesion, on the membrane properties, ionic currents, and synaptic physiology of mutant embryonic cortical neurons remains largely unknown
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