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Development and disease: Quantification of inhibitory and excitatory synaptic structures in primary auditory cortex during adolescence and in schizophrenia

Moyer, Caitlin E (2013) Development and disease: Quantification of inhibitory and excitatory synaptic structures in primary auditory cortex during adolescence and in schizophrenia. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Individuals with schizophrenia demonstrate auditory processing impairments that localize to primary auditory cortex, and likely contribute to disruptions of higher level processes and resultant disability. To inform the development of new treatments and preventative measures, we sought to understand which synapse populations contribute to primary auditory cortex pathology. We used quantitative fluorescence microscopy to assess intracortical excitatory, thalamocortical, and inhibitory boutons in primary auditory cortex deep layer 3 of individuals with schizophrenia. We found that intracortical excitatory and thalamocortical boutons are unaltered in schizophrenia despite reduced density of dendritic spines, their primary postsynaptic targets. However, levels of the 65 kiloDalton isoform of glutamate decarboxylase (GAD65) protein are reduced within inhibitory boutons in primary auditory cortex of subjects with schizophrenia. Further, reductions in within-bouton GAD65 protein are correlated with previously measured reductions in spine density.

As the onset of schizophrenia typically occurs during late adolescence and young adulthood, adolescence represents a potential window of opportunity for preventing the pathophysiology underlying symptom onset. However, adolescent trajectories of auditory cortex synaptic components and associated auditory cortex functional changes that could be targeted for prevention have not been characterized. In mouse auditory cortex, we found that spine and excitatory bouton numbers decrease between early adolescence and young adulthood followed by reduction of within-bouton GAD65 protein levels between late adolescence and young adulthood. As a behavioral readout of auditory cortex function, we measured gap-mediated prepulse inhibition of the acoustic startle reflex (gap-PPI) in mice between early adolescence and young adulthood. Gap-PPI responses increase during adolescence, suggesting that adolescent development of auditory cortex synapses contributes to auditory cortex functional maturation.

Our findings suggest that spine and within-bouton GAD65 protein deficits are related pathological features of primary auditory cortex in schizophrenia, and that within-bouton GAD65 protein declines subsequent to the onset of auditory cortex spine pruning between early adolescence and young adulthood. From these observations, we propose a model where excessive spine pruning in auditory cortex leads to an excessive reduction in within-bouton GAD65 protein. Testing this model will promote development of strategies to prevent auditory cortex pathophysiology and downstream perceptual and cognitive deficits in schizophrenia.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Moyer, Caitlin Ecem46@pitt.eduCEM46
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorSweet, Robert Asweetra@upmc.eduSWEET
Committee ChairSibille, Etienneets7@pitt.eduETS7
Committee MemberFish, Kennethfishkn@upmc.edu
Committee MemberHolt, Lorilholt@andrew.cmu.edu
Committee MemberThiels, Eddathiels@pitt.eduTHIELS
Committee MemberJavitt, DanielJavitt@NKI.RFMH.ORG
Date: 19 September 2013
Date Type: Publication
Defense Date: 28 August 2013
Approval Date: 19 September 2013
Submission Date: 18 September 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 278
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: neurodevelopment; quantitative fluorescence microscopy; prepulse inhibition; adolescent synapse pruning; kalirin; mouse model
Date Deposited: 19 Sep 2013 14:08
Last Modified: 19 Dec 2016 14:41
URI: http://d-scholarship.pitt.edu/id/eprint/19786

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