Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

Abstract

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, have been shown to cause a novel neurodevelopmental syndrome and increase the risk for schizophrenia. To study the effect of decreased SETD1A function in human cells, we generated excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was mainly characterized by an overly synchronized network. In individual neurons, this network phenotype was reflected by increased somatodendritic complexity and elevated synaptic connectivity. We found that this network phenotype was driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling revealed perturbations in gene sets associated with schizophrenia, synaptic transmission and glutamatergic synaptic function. At the molecular level, we identified specific changes in the cAMP/PKA pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, using pharmacological experiments targeting the cAMP pathway we were able to rescue the network deficits in SETD1A+/- cultures. In conclusion, our results illuminate key molecular, cellular and network abnormalities caused by SETD1A haploinsufficiency and demonstrate a direct link between SETD1A and the cAMP-dependent pathway in human neurons.

The iPSC perspective on schizophrenia

“…The studies also provided not only evidence of excitatory postsynaptic deficits, concordantly with postmortem and genetic findings [31,144], but also emerging evidence of altered inhibitory synaptogenesis [88,129]. The possible contribution of altered cAMP signaling to neuronal dysfunction has been acknowledged clinically and studied recently using neuronal in vitro models of schizophrenia [139,141].…”

“…PDE4 inhibitors have also been shown to improve deficits in MMN and working memory-related theta activity alterations clinically [140]. Interestingly, preliminary data linked schizophreniaassociated SETD1A mutation to hyperactivity in the cAMP/PKA pathway in iPSC-derived excitatory neurons [141]. As done in this study, it is critical to consider cell type specificity when investigating neurobiological phenomena arising from excitatory-inhibitory neuronal interactions.…”