Abstract
The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K+ and Na+ currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by clozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K+ and Na+ channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients.
Highlights
Clozapine is one of the most effective antipsychotic agents (Meltzer, 2013; Okhuijsen-Pfeifer et al, 2018)
Neural differentiation using a standardized protocol (Figure 2A) generated primarily glutamatergic neurons appearing at 30 days (Figure 2B)
We found further that other gene sets that were down-regulated in clozapine responsive (CLZ-R) SCZ neurons were up-regulated by clozapine pretreatment, including those involved in retrograde endocannabinoid signaling, morphine addiction, and GABAergic, dopaminergic, and glutamatergic synapses (Figure 6C, Supplementary Figure 3, and Table 2)
Summary
Clozapine is one of the most effective antipsychotic agents (Meltzer, 2013; Okhuijsen-Pfeifer et al, 2018). About 30% of treatment-resistant schizophrenia patients receive clozapine (Farooq and Taylor, 2011). The processes behind clozapine nonresponse are unknown, and the mechanisms underlying selective clinical effects of clozapine remain unclear (Meltzer, 1994; Lameh et al, 2007; Dziedzicka-Wasylewska et al, 2008; Lee et al, 2017; Nucifora et al, 2017). Progress in understanding the treatment and pathology of schizophrenia was hindered by the inability to study ongoing disease processes in human pathological tissue. Human post-mortem and imaging studies indicate pathology in several brain cell types (Falk et al, 2016; van Erp et al, 2018). Pyramidal glutamatergic neurons—principal elements of cortical microcircuits—have reduced soma sizes and dendritic arbors (Harrison, 2000; Glausier and Lewis, 2013; van Erp et al, 2018). Changes in GABAergic interneurons lead to perturbations of coordinated activity in cortical microcircuits, and, a reduced ability to integrate inputs from other cortical areas, with subsequent abnormalities in corticocortical interactions (Garey, 2010; Gonzalez-Burgos and Lewis, 2012; Harrison, 2015; Datta and Arnsten, 2018)
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