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| The cognitive processes mediated by the DLPFC undergo a protracted period of postnatal maturation which extends from the perinatal through the adolescent 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 that occur during early postnatal life and adolescence (Figures 1 and 2). 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. |
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| Figure 1. Pre- and postsynaptic markers of chandelier neuron inputs to the axon initial segment of pyramidal neurons. A,B. Immunoreactivity for GABA transporter 1 (GAT1) and parvalbumin clearly identifies vertical arrays of chandelier neuron axon terminals (cartridges) that are located below the cell bodies of unlabeled pyramidal neurons. C. Immunoreactivity for the 2 subunit of the GABA-A receptor is localized postsynaptically, in the axon initial segment of pyramidal neurons. (Cruz DA, Eggan SM, Lewis DA: Postnatal development of pre- and post-synaptic GABA markers at chandelier cell connections with pyramidal neurons in monkey prefrontal cortex. J Comp Neurol 465:385-400, 2003.) |
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| Figure 2. Postnatal development of chandelier
neuron inputs. The axon terminals of chandelier neurons are vertical
arrays of boutons (cartridges) that are immunoreactive for parvalbumin
(PV) or GABA membrane transporter 1 (GAT1), and outline the axon initial
segment of pyramidal neurons. Although the developmental time course
differs somewhat for these two markers, as illustrated in the diagram,
the density of labeled cartridges is low in the DLPFC of newborn monkeys,
increases to reach a peak before the onset of puberty, and then declines
markedly during adolescence (shaded area between 15 and 42 months of
age) to adult levels. These density changes in PV- and GAT-immunoreactive
cartridges seem to reflect developmental shifts in the concentration
of these proteins (and so in the detectability of cartridges) as cartridges
are readily visualized with the Golgi technique over this same time
period. Interestingly, the peak and subsequent decline in the density
of labeled cartridges occurs prior to the age at which the peak density
of PV-immunoreactive varicosities-putative axon terminals from the wide
arbor class of PV-expressing GABA neurons-is achieved. Postsynaptically,
the detectability of the 2 subunit of the GABAA receptor in pyramidal
neuron axon initial segments is high at birth, and then markedly declines
during adolescence before stable adult levels are achieved. The marked
developmental changes in these pre- and post-synaptic markers of inhibition
at the inputs from chandelier and wide arbor cells to the perisomatic
region of pyramidal neurons indicate that the capacity to synchronize
pyramidal neuron output in the DLPFC might be in substantial flux until
adulthood. Consequently, the protracted developmental time course of
improvements in performance on working memory tasks might depend on
both refinements in the number of excitatory connections among pyramidal
neurons and changes in their proximal inhibitory inputs. These developmental
changes during adolescence might contribute to unmasking the consequences
of inherited abnormalities in the regulation of GABA mediated neurotransmission
and might help to explain why certain life experiences during adolescence
(for example, stress or cannabis exposure) seem to increase the risk
for schizophrenia. (Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nature Reviews Neuroscience 6:312-324, 2005.) |
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) 624-3934 - Fax: (412) 624-9910 |