One of the major impediments to psychiatric disorder's research is the lack of relevant animal and cell models for the disorder. We developed the first human in vitro system using induced pluripotent stem cells iPSCs) from patients to understand the molecular and cellular mechanism underlying psychiatric disorders. IPSC can be coaxed to differentiate in different cell types of the nervous system. Strong evidences suggest that several psychiatric disorders are diseases of synapses, leading to defects in network synchronization. Thus, the majority of researchers have focused on neurons. Long thought to be primarily passive support cells, recent studies have established that astrocytes secrete signaling molecules that powerfully stimulate the formation and function of synapses throughout the brain. Therefore, by studying neurons and astrocytes separately we showed that neurons alone have limited ability to form synapses. Astrocytes' dysfunctions are now known to be associated with many psychiatric disorders, including schizophrenia. Increase or decrease in the levels of plasticity-related proteins available to active synapses in neurons may cause changes in synaptic connectivity, compromising network performance and producing cognitive impairment. Our data revealed the negative influence of patient-derived astrocytes on homeostasis of control neurons. Moreover, by plating patient-derived neurons with normal control astrocytes, we were able to rescue synaptogenesis, spine density, soma size and neuronal arborization. In this proposal, we hypothesize that astrocytes may contribute to mental disease progression. We will analyze neurons and astrocytes from isogenic iPSC cells carrying genetic alterations that are common between autism and schizophrenia, hoping to reveal novel molecular pathways that could be used as novel therapeutical targets. Our work may also illuminate possible differences in drug responsiveness in different patients and potentially define a molecular signature resulting from genetic variants, which could predict disorder outcome. We believe that our experiments are designed to rigorously test a specific hypothesis underlying neuronal reaction to psychiatric disorders and will have a positive impact on the lives of patients.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
