title: NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure.
abstract: Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6 months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: tobias.halene@mountsinai.org.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Halene
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kozlenkov
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Behnam
authors.initials: B
authors.lastname: Javidfar
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Dincer
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Royce
authors.initials: R
authors.lastname: Park
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wiseman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Croxson
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Eustathia Lela
authors.initials: EL
authors.lastname: Giannaris
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Dracheva
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Hemby
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D002452:Cell Count; D003024:Clozapine / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D066128:Gray Matter / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008251:Macaca; D008279:Magnetic Resonance Imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size; D011897:Random Allocation; D066127:White Matter / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D003024:Clozapine; D006220:Haloperidol
keywords: Antipsychotic; Clozapine; Flow cytometry; Monkey; Schizophrenia; White matter