Cortical Development Title Link to Cognitive Function Description

  • The cognitive processes mediated by the DLPFC undergo a protracted course of postnatal maturation extending from birth through adolescence, the periods of development that appear to be critical for the manifestation of the clinical syndrome of schizophrenia.
  • Consequently, the second component of our research strategy involves characterizing the postnatal development of monkey DLPFC circuitry. Special emphasis is placed on the maturational events, such as synaptogenesis and synaptic pruning, which occur during early postnatal life and adolescence, respectively.
  • The timing and regional-, laminar-, and cell type-specificity of these processes are examined for their possible contribution to the emergence and refinement of the types of cognitive abilities that are disturbed in schizophrenia.
  • These studies are conducted in collaboration with Program faculty members Dr. Guillermo Gonzalez-Burgos and Dr. Ken Fish.
Recent Findings:
  • Analysis of inhibitory postsynaptic currents mediated through GABAA receptors (GABAA-R) reveals that the decay of GABAA-R IPSCs shortens by prepubertal age, while their amplitude increases until peripuberty.  Simulations in a computational model network show that the developmental changes in GABAA-R IPSCs properties predict that mature levels of gamma band power are attained at late stages of development (read more).
  • Levels of mRNA of the transcription factor Lhx6 significantly decline from the perinatal to prepubertal period and then stabilize in the DLPFC of monkeys.  An excessive early postnatal decrease in Lhx6 mRNA may contribute to Lhx6 mRNA deficits in schizophrenia (read more).
  • Multi-label confocal microscopy has revealed that the boutons of parvalbumin (PV)-containing chandelier neurons undergo a different developmental trajectory than the boutons of the PV-containing basket cells and that the levels of PV protein also differ across development in these two populations of PV-containing boutons. These findings suggest cell-type specific mechanisms of maturation of PV-containing GABAergic boutons in monkey PFC (read more).
  • The expression of GABAA receptor subunit mRNAs in layer 3 pyramidal neurons in monkey DLPFC changes substantially over postnatal development, whereas glutamate receptor subunit changes are modest. Some transcripts (e.g.GABAA α1) progressively increase in expression from birth until adulthood, whereas others (e.g. GABAA α2) decline across the same period. These findings indicate that the development of GABAA receptor subunit expression in DLPFC pyramidal neurons is protracted and subunit- and layer-specific and suggest that these trajectories might contribute to the molecular basis for the maturation of working memory (read more).
. Ongoing Projects:
  • Use of single-cell laser capture microdissection, in conjunction with qPCR and gene expression profiling, to characterize the developmental trajectories of molecular transcripts regulating GABA and glutamate inputs to DLPFC pyramidal cells.
  • Determination of how different types of inhibitory inputs to layer 3 pyramidal cells are refined during postnatal development using in vitro slice preparations of monkey DLPFC tissue.

• Translational Neuroscience Program •
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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
Pittsburgh, Pennsylvania 15213-2593
Phone: (412) 624-3894 - Fax: (412) 624-9910