The class of gamma-aminobutyric acid (GABA)ergic inhibitory local circuit neurons (LCNs) that contain the calcium binding protein (CBP) parvalbumin (PV), which include basket and chandelier cells, exhibit fast-spiking activities and furnish perisomatic and axo-axonic innervation of pyramidal neurons, respectively. They also receive glutamatergic inputs from corticocortical (CC) and thalamocortical (TC) terminals. In addition, they are electrically coupled via gap junctions. Via chemical and electrical synaptic connections, PV neurons regulate the oscillatory dynamics in the cerebral cortex. Because disruption of cortical oscillatory dynamics may underlie many of the neurocognitive deficits of schizophrenia (SCZ), we postulate that the integrity of PV neurons may be compromised in this disorder. To test the hypothesis that, in the prefrontal cortex, glutamatergic inputs to PV neurons via N-methyl-D-aspartate (NMDA) receptors may be selectively altered, in a cohort of 21 SCZ and 21 matched normal control subjects, we will: (1) Colocalize the mRNA for the NMDA NR2A subunit and the mRNA for PV, calbindin (CB), which is a CBP that is expressed by a class of LCNs that target the distal dendrites of PNs, or cholecystokinin (CCK), which identifies a class of regular-spiking basket cells that do not contain PV, and (2) Examine the appositions of CC and TC terminals, labeled by an antibody against the vesicular glutamate transporter vGluTI and 2, respectively, on PV- and CCK-immunoreactive (ir) neurons. Furthermore, in order to shed light on whether PV axonal terminals may be selectively altered, we will: (1) Colocalize the mRNA for the GABA transporter GAT-1 and the mRNA for PV, CB, or CCK, and (2) Utilize quantitative real-time reverse transcriptase polymerase chain reaction to quantitate the mRNA for GABAA receptor alpha 1 and 2 subunits, which are preferentially enriched in synapses formed by basket and chandelier cells, respectively, in laser-captured pyramidal neurons. Finally, we will quantitate the amount of mRNA for brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in laser-captured pyramidal neurons and PV- or CB-ir cells, respectively, in order to test the hypothesis that deficient BDNF/TrkB signaling may contribute to the selective deficits of PV neurons. Together, these experiments may provide conceptually novel insight into how neurocognitive deficits of SCZ could potentially be corrected by re-calibration of PV neuronal activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH076060-03
Application #
7477921
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2006-08-01
Project End
2010-05-31
Budget Start
2008-08-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$246,222
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Sonntag, Kai-Christian; Woo, Tsung-Ung W (2018) Laser microdissection and gene expression profiling in the human postmortem brain. Handb Clin Neurol 150:263-272
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Mauney, Sarah A; Woo, Tsung-Ung W; Sonntag, Kai C (2018) Cell Type-Specific Laser Capture Microdissection for Gene Expression Profiling in the Human Brain. Methods Mol Biol 1723:203-221
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Bitanihirwe, Byron K Y; Woo, Tsung-Ung W (2014) Perineuronal nets and schizophrenia: the importance of neuronal coatings. Neurosci Biobehav Rev 45:85-99

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