Abstract
Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron–glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron–glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron–glia interactions.
Highlights
This co-localization of ERβ with hippocampal GABAergic neurons may explain, at least in part, the fact that hippocampal GABAergic neurons are more affected in men than in women with SCZ [50] and the fact that, in general, women with SCZ experience less cognitive problems than men [51], since these cells produce gamma-band oscillations that are essential for cognitive functions [52]
Calcium-related alterations in the distribution of membrane phospholipids [111]. This is in line with the fact that among the most consistent genome-wide associations studies (GWASs) findings are associations between SNPs in the α1 subunit (CACNA1C) of the voltage-gated L-type Ca2+ channel (LTCC) Cav1.2 and SCZ and bipolar disorder (BIP) [112], and that several proteins related to Ca2+ metabolism are found altered in individuals with SCZ [113]
More recent models hypothesize that a dysregulation of glutamatergic and GABAergic neurotransmission have a primary role in the pathophysiology of SCZ [27,210] and BIP [216,217], where dopaminergic imbalance would be a secondary effect [218]
Summary
Combining E2 or selective estrogen receptor modulators (SERMs) with antipsychotics or mood stabilizers have been successful therapeutic strategies against SCZ and BIP symptoms [11,22,23] This underscores the importance of a more detailed understanding of the mechanisms underlying the neuromodulatory effect of E2 in mental illnesses, which remains largely unknown, and holds the potential for improved treatments for both male and female patients with SCZ and BIP [24].
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