BACKGROUND: Schizophrenia is associated with perceptual and physiological auditory processing impairments that may result from primary auditory cortex excitatory and inhibitory circuit pathology. High-frequency oscillations are important for auditory function and are often reported to be disrupted in schizophrenia. These oscillations may, in part, depend on upregulation of gamma-aminobutyric acid synthesis by glutamate decarboxylase 65 (GAD65) in response to high interneuron firing rates. It is not known whether levels of GAD65 protein or GAD65-expressing boutons are altered in schizophrenia. METHODS: We studied two cohorts of subjects with schizophrenia and matched control subjects, comprising 27 pairs of subjects. Relative fluorescence intensity, density, volume, and number of GAD65-immunoreactive boutons in primary auditory cortex were measured using quantitative confocal microscopy and stereologic sampling methods. Bouton fluorescence intensities were used to compare the relative expression of GAD65 protein within boutons between diagnostic groups. Additionally, we assessed the correlation between previously measured dendritic spine densities and GAD65-immunoreactive bouton fluorescence intensities. RESULTS: GAD65-immunoreactive bouton fluorescence intensity was reduced by 40% in subjects with schizophrenia and was correlated with previously measured reduced spine density. The reduction was greater in subjects who were not living independently at time of death. In contrast, GAD65-immunoreactive bouton density and number were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia. CONCLUSIONS: Decreased expression of GAD65 protein within inhibitory boutons could contribute to auditory impairments in schizophrenia. The correlated reductions in dendritic spines and GAD65 protein suggest a relationship between inhibitory and excitatory synapse pathology in primary auditory cortex.
BACKGROUND:Schizophrenia is associated with perceptual and physiological auditory processing impairments that may result from primary auditory cortex excitatory and inhibitory circuit pathology. High-frequency oscillations are important for auditory function and are often reported to be disrupted in schizophrenia. These oscillations may, in part, depend on upregulation of gamma-aminobutyric acid synthesis by glutamate decarboxylase 65 (GAD65) in response to high interneuron firing rates. It is not known whether levels of GAD65 protein or GAD65-expressing boutons are altered in schizophrenia. METHODS: We studied two cohorts of subjects with schizophrenia and matched control subjects, comprising 27 pairs of subjects. Relative fluorescence intensity, density, volume, and number of GAD65-immunoreactive boutons in primary auditory cortex were measured using quantitative confocal microscopy and stereologic sampling methods. Bouton fluorescence intensities were used to compare the relative expression of GAD65 protein within boutons between diagnostic groups. Additionally, we assessed the correlation between previously measured dendritic spine densities and GAD65-immunoreactive bouton fluorescence intensities. RESULTS:GAD65-immunoreactive bouton fluorescence intensity was reduced by 40% in subjects with schizophrenia and was correlated with previously measured reduced spine density. The reduction was greater in subjects who were not living independently at time of death. In contrast, GAD65-immunoreactive bouton density and number were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia. CONCLUSIONS: Decreased expression of GAD65 protein within inhibitory boutons could contribute to auditory impairments in schizophrenia. The correlated reductions in dendritic spines and GAD65 protein suggest a relationship between inhibitory and excitatory synapse pathology in primary auditory cortex.
Authors: J S Kwon; B F O'Donnell; G V Wallenstein; R W Greene; Y Hirayasu; P G Nestor; M E Hasselmo; G F Potts; M E Shenton; R W McCarley Journal: Arch Gen Psychiatry Date: 1999-11
Authors: Y Hirayasu; R W McCarley; D F Salisbury; S Tanaka; J S Kwon; M Frumin; D Snyderman; D Yurgelun-Todd; R Kikinis; F A Jolesz; M E Shenton Journal: Arch Gen Psychiatry Date: 2000-07
Authors: A Guidotti; J Auta; J M Davis; V Di-Giorgi-Gerevini; Y Dwivedi; D R Grayson; F Impagnatiello; G Pandey; C Pesold; R Sharma; D Uzunov; E Costa; V DiGiorgi Gerevini Journal: Arch Gen Psychiatry Date: 2000-11
Authors: Micah A Shelton; Jason T Newman; Hong Gu; Allan R Sampson; Kenneth N Fish; Matthew L MacDonald; Caitlin E Moyer; James V DiBitetto; Karl-Anton Dorph-Petersen; Peter Penzes; David A Lewis; Robert A Sweet Journal: Biol Psychiatry Date: 2015-01-30 Impact factor: 13.382
Authors: Matthew L MacDonald; Megan Garver; Jason Newman; Zhe Sun; Joseph Kannarkat; Ryan Salisbury; Jill Glausier; Ying Ding; David A Lewis; Nathan Yates; Robert A Sweet Journal: JAMA Psychiatry Date: 2020-01-01 Impact factor: 21.596
Authors: Caitlin E Moyer; Kristen M Delevich; Kenneth N Fish; Josephine K Asafu-Adjei; Allan R Sampson; Karl-Anton Dorph-Petersen; David A Lewis; Robert A Sweet Journal: Schizophr Res Date: 2013-07-02 Impact factor: 4.939
Authors: Matthew L MacDonald; Ying Ding; Jason Newman; Scott Hemby; Peter Penzes; David A Lewis; Nathan A Yates; Robert A Sweet Journal: Biol Psychiatry Date: 2014-11-26 Impact factor: 13.382
Authors: Ahmad Alhourani; Kenneth N Fish; Thomas A Wozny; Vivek Sudhakar; Ronald L Hamilton; R Mark Richardson Journal: J Neurophysiol Date: 2019-12-04 Impact factor: 2.714
Authors: Matthew L MacDonald; Jamil Alhassan; Jason T Newman; Michelle Richard; Hong Gu; Ryan M Kelly; Alan R Sampson; Kenneth N Fish; Peter Penzes; Zachary P Wills; David A Lewis; Robert A Sweet Journal: Am J Psychiatry Date: 2017-03-31 Impact factor: 18.112
Authors: Caitlin E Moyer; Susan L Erickson; Kenneth N Fish; Edda Thiels; Peter Penzes; Robert A Sweet Journal: Cereb Cortex Date: 2015-03-10 Impact factor: 5.357