Year: 2016
Type: dissertation
Study design: Observational Study
Abstract: Cognitive dysfunction is a core and clinically-critical feature of schizophrenia. Certain cognitive deficits, such as impaired working memory, appear to emerge from altered gamma oscillations in the dorsolateral prefrontal cortex (DLPFC). Cortical gamma oscillations require the activity of parvalbumin (PV) interneurons and reduced PV interneuron activity in schizophrenia has been proposed to be due to deficient excitatory drive to these neurons. Synaptic pruning coincides with the period in which individuals with schizophrenia typically present their first clinical symptoms and thus an excessive pruning of excitatory inputs to PV interneurons in the DLPFC during development could provide the neural substrate for altered prefrontal gamma oscillations and working memory dysfunction in schizophrenia. However, evidence for pruning or pathogenic loss of excitatory inputs to PV interneurons in development and schizophrenia, respectively, and molecular mechanisms underlying these processes have not been identified. The formation of excitatory synapses on PV interneurons is mediated by ErbB4 signaling pathway. ErbB4 transcript is alternatively spliced and each splice variant is associated with different functional effects. In schizophrenia, the total ErbB4 expression is unaltered, but alternative splicing of ErbB4 is dysregulated, suggesting that ErbB4 splicing shifts may provide molecular mechanisms for modulating the excitatory synapse number on PV interneurons. Using a top-down translational approach, I first characterized the association between dysregulated ErbB4 splicing shifts and fewer excitatory inputs to PV interneurons in a human cohort of comparison subjects and schizophrenia subjects. Then I assessed the developmental context of this relationship in a cohort of non-human primates with different ages. Finally, I investigated the cause-and-effect relationship between ErbB4 splicing shifts and excitatory synapse number on PV interneurons using rat primary neuronal culture. Data from these different experimental systems converge onto the hypothesis that developmental shifts in ErbB4 splicing induce pruning of excitatory synapses on PV interneurons and deficits in this process result in a loss of excitatory inputs to PV interneurons in schizophrenia. Therefore, work from this dissertation reinforces the view that schizophrenia is a neurodevelopmental disorder with disturbances in the maturation of prefrontal cortical circuitry.
Author: Daniel W. Chung
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2582830637