White Matter Neurons Numbers and Densities Across the Human Lifespan, Including the Potential Role(s) of Antipsychotic Drugs

Halene T, Dincer A, Kozlenkov A, Croxson P, Mitchell A, Jiang Y, Lin C, Giannaris E, Guo Y, Akintobi A, Lessard A, Hof P, Roussos P, Dracheva S, Hemby S, Bunney W, Akbarian S
Annual Meeting of the American College of Neuropsychopharmacology. 2015.


Background: Increased numbers and densities of subcortical white matter neurons (WMN) have been reported for a subset of cases diagnosed with schizophrenia and in non-human primates chronically exposed to antipsychotic drugs (APD). The underlying cellular and molecular mechanisms remain unresolved: This alteration could reflect a fixed lesion of early brain development, but it is not known whether there is ongoing dynamic regulation of WMN numbers in the adult brain.

Methods: We determined the proportion of neuronal nuclei in frontal lobe white matter of 104 brains, including 65 controls from newborn to 93 years of age and 39 cases diagnosed with schizophrenia from 22 to 87 years of age. Based on the results – an overall decline in WMN over the lifespan but an increased proportion of WMN in a subset of patients with schizophrenia - we subsequently explored the effect of antipsychotic drugs. 26 adult macaque monkeys were exposed for six 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 with cell-type specific transcripts.

Results: In human subjects, normal aging was associated with a decline in the WMN ratio after early childhood. Interestingly, 15% (6/39) subjects with schizophrenia, exceeded the 99th percentile of controls. Normal aging was associated with a decline in the WMN ratio after early childhood whereas the excess WMN in schizophrenia showed no association with age. After clozapine exposure in non-human primates, the WMN ratio increased in subcortical white matter, in conjunction with a subtler but not 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 APD exposure. Frontal lobe gray and white matter volumes remained indistinguishable between APD and control groups.

Conclusions: Frontal lobe WMN are subject to decline during the course of normal maturation. A subset of subjects with schizophrenia has increased WMN independent of age. In non-human primates, chronic clozapine exposure increases the proportion of WMN in frontal subcortical white matter pointing towards a modulatory effect of certain antipsychotics on prefrontal cell composition.