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In schizophrenia, impaired working memory is associated with transcriptome alterations in layer 3 pyramidal neurons in the dorsolateral prefrontal cortex. Distinct subtypes of layer 3 pyramidal neurons that send axonal projections to the dorsolateral prefrontal cortex in the opposite hemisphere (callosal projection neurons) or the parietal cortex in the same hemisphere (ipsilateral projection neurons) play critical roles in working memory. However, how the transcriptomes of these layer 3 pyramidal neuron subtypes might shift during late postnatal development when working memory impairments emerge in individuals later diagnosed with schizophrenia is not known. 

Pitt Psychiatry investigators including Dominique Arion (Research Principal Senior); John Enwright, PhD (Research Assistant Professor of Psychiatry); Guillermo Gonzalez-Burgos, PhD (Associate Professor of Psychiatry); and David Lewis, MD (Distinguished Professor of Psychiatry and Neuroscience, Thomas Detre Professor of Academic Psychiatry), designed a study to  characterize and compare the transcriptome profiles of callosal projection and ipsilateral projection layer 3 pyramidal neurons across developmental transitions from prepuberty to adulthood in macaque monkeys. The team used laser microdissection to individually dissect retrogradely-labeled layer 3 pyramidal neurons in the dorsolateral prefrontal cortex that project to the ipsilateral posterior parietal cortex or the contralateral dorsolateral prefrontal cortex from prepubertal, post-pubertal, and adult animals. Pools of these neurons were subjected to RNAseq analyses.

In a paper published in the American Journal of Psychiatry, the investigators identified numerous shifts during late postnatal development in the gene expression profiles of both ipsilateral projection and callosal projection neurons. The team’s findings demonstrate that 1) the transcriptomes of callosal projection and ipsilateral projection layer 3 pyramidal neurons substantially differ at each of the three ages studied; 2) the number of genes and gene pathways differentiating callosal projection from ipsilateral projection layer 3 pyramidal neurons increases with age; 3) these age-related differences between cell types appear to be the consequence of developmental shifts in gene expression in both cell types; and 4) the larger shift in gene expression took place between prepubertal and post-pubertal animals for ipsilateral projection layer 3 pyramidal neurons, but between post-pubertal and adult animals for callosal projection layer 3 pyramidal neurons.

“In concert with other data (e.g., the timing of dendritic spine pruning on layer 3 pyramidal neurons), these findings suggest that callosal projection neurons might be at particular risk for developmental alterations, and thus contribute to the emergence of working memory impairments during adolescence, in people later diagnosed with schizophrenia,” said Dr. Lewis, the study’s senior and corresponding author.

Cell Type–Specific Profiles and Developmental Trajectories of Transcriptomes in Primate Prefrontal Layer 3 Pyramidal Neurons: Implications for Schizophrenia
Arion D, Enwright JF, Gonzalez-Burgos G, Lewis DA.
American Journal of Psychiatry, Volume 181, Number 10. https://doi.org/10.1176/appi.ajp.20230541