Role of fast spiking interneurons in network synchronization and development

点击翻译按钮获取中文摘要

SUMMARY The brain's ability to properly process information is dependent on the ability of neuronal networks to synchronize and generate oscillations in the gamma band (30-80 Hz). The ability of neuronal networks to generate proper gamma oscillations matures slowly. Developing networks are susceptible to environmental insults that could alter their development leading to abnormal oscillations. Abnormalities in gamma oscillations are implicated in the pathology of mental health disorders including schizophrenia and bipolar disorder. In many of these disorders, dysregulated inhibition is thought to give rise to abnormalities in network function. Fast spiking interneurons (FSI) are a subset of GABAergic inhibitory neurons known to be crucial for the proper generation of gamma oscillations. Abnormal FSI function has been observed in multiple animal models of schizophrenia. Rodent models using antagonists of N-methyl-D-aspartate receptors (NMDAR) mimic many of the phenotypes observed in schizophrenia including the late age onset of cognitive deficits and abnormalities in gamma oscillations. Inhibition of NMDARs can also lead to abnormalities in FSI maturation and physiology, but the impact of NMDAR antagonists on the ability of FSIs' to generate coordinated network activity remains poorly understood. The objective of this proposal is to determine the role of NMDARs in the capacity of FSIs to generate and sustain coordinated network activity. The short-term training goals for the F99 phase of this proposal are to determine how NMDARs influence FSIs' maturation and physiology leading to impaired network function. This will be achieved by using microelectrode arrays to measure and manipulate synchronous network activity in brain sections obtained from adult animals after pharmacological blockade of NMDARs. I will use protein quantification through western blots and immunohistochemistry to identify changes in proteins that could contribute to the physiological impairment of FSIs. The F99 phase will provide a foundation for the K00 phase in which I will focus on determining how the intrinsic properties of FSIs allow them to generate and maintain synchronous network activity. A combination of single cell, network recordings, in vivo manipulation of FSIs' activity, and in silico network modeling will be incorporated to identify the different properties that contribute to synchronize network activity. The F99 and K00 training phases will provide a strong foundation for my long-term goal of becoming an independent academic researcher focused on determining how neurons participate in neuronal networks and the impact of environmental insults. This proposal will help build upon our understanding of the fundamental principles that govern how neurons interact to form functional networks. Additionally, it will help advance our understanding of the link between molecular and network alteration underlying complex mental health disorders like schizophrenia.