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Development of the Prefrontal Cortex During Adolescence: Insights Into Vulnerable Neural Circuits in Schizophrenia David A

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Development of the Prefrontal Cortex During Adolescence: Insights Into Vulnerable Neural Circuits in Schizophrenia David A ELSEVIER REVIEW Development of the Prefrontal Cortex during Adolescence: Insights into Vulnerable Neural Circuits in Schizophrenia David A. Lewis, M.D. -------- ----------- Multiple lines of evidence suggest that the prefrontal cortex article reviews data demonstrating that these late is a site of dysfunction in schizophrenia. In addition, one of developmental changes are selective for particular neural the characteristics of this disorder is the tendency for elements in the prefrontal cortex and that they are clinical symptoms to appear first during late adolescence or synaptically linked. It is suggested that these neural early adulthood. Recent studies in nonhuman primates have elements comprise a functional circuit that is likely to be shown that the connectivity of the prefrontal cortex is especially vulnerable in schizophrenia, a hypothesis that can substantially refined during adolescence, suggesting that be directly tested in postmortem studies. these developmental changes may be critical for the [Neuropsychophannacology 16, 385-398, 1997] appearance of the clinical features of schizophrenia. This © 1997 American College of Neuropsychopharmacology KEY WORDS: Cortical development; Dopamine; Local circuit schizophrenia (Levin 1984; Weinberger et al. 1986; Park neurons; Prefrontal cortex; Pyramidal neurons; and Holzman 1992), although controversy exists regarding Schizophrenia the interpretation of some findings (Chua and McKenna The symptoms of schizophrenia appear to be associated 1995; Cur and Cur 1995). The results of recent in vivo with dysfunction and structural changes in a number of imaging and postmortem studies suggest that DLPFC brain regions, as well as in the connections that link dysfunction may be related to alterations in the synap­ these regions (see Friston and Frith 1995; Pearlson et al. tic connectivity of this region. For example, prefrontal 1996 for review). Understanding the pathophysiology cortex (PFC) gray matter volume has been found to be of this disorder will ultimately require an appreciation decreased in schizophrenic subjects in some (Shelton et of how abnormalities in one brain region produce and/ al. 1988; Breier et al. 1992; Zipursky et al. 1992; An­ or result from disturbances in other brain areas. How­ dreasen et al. 1994b; Schlaepfer et al. 1994), but not all ever, knowledge of the circuitry abnormalities within (Wible et al. 1995) MRI structural studies, and MRI an affected region is a critical step in this process as the spectroscopic investigations have found evidence for a output from a given region is dependent on the flow of decrease in synaptic building blocks in the DLPFC information processing within that region. (Pettegrew et al. 1991; Stanley et al. 1995). Similarly, Multiple lines of evidence suggest that the dorsolat­ postmortem studies have found that cell-packing den­ eral prefrontal cortex (DLPFC) is a site of dysfunction in sity is increased and cortical thickness decreased in the DLPFC of schizophrenic subjects (Pakkenberg 1987; From the Departments of Psychiatry and Neuroscience, University Daviss and Lewis 1995; Selemon et al. 1995). In addi­ of Pittsburgh, Pittsburgh, Pennsylvania. tion, the total number of cortical neurons does not ap­ Address correspondence to: David A. Lewis, M.D., BST W1650, pear to be altered in schizophrenia (Pakkenberg 1993; Western Psychiatric Institute and Clinic, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213. Akbarian et al. 1995), although some investigators have Received September 10, 1996; accepted November 26, 1996. observed decreased numbers of certain populations of NECROPSYCHOPHARMACOLOG\ 1997-VOL. 16, Ml. h © 1997 American College of Neuropsychopharmacology Published bv Elsevier Science Inc. 0893-133X/97 /$17.00 655 Avenue,of the Americas, New York, NY 10010 PII S0893-133X(96 )00277-1 386 D. A Lewis NEUROPSYCHOPHARMACOLOGY 1997-VOL. 16, NO. 6 prefrontal neurons (Benes et al. 1991). Together, the overt symptoms of schizophrenia by some time (Haas presence of increased cell packing density without a and Sweeney 1992; Larsen et al. 1996). Thus, develop­ change in neuron number suggests that the DLPFC mental events occurring during the second decade of neuropil, which includes the axon terminals, small den­ life may play a critical role in the appearance of DLPFC drites, and dendritic spines that are the components of dysfunction in schizophrenia. most cortical synapses, is diminished in schizophrenia. The following sections review recent studies on the Consistent with this interpretation, levels of the syn­ normal development of the primate DLPFC during ad­ apse-associated protein synaptophysin have been re­ olescence. Based on these findings, I propose a provi­ ported to be decreased in the DLPFC of schizophrenic sional, but testable, model of a specific set of synapti­ subjects (Karson et al. 1996; Glantz and Lewis in press; cally linked components of DLPFC circuitry that is Perrone-Bizzozero et al. 1996). However, understand­ altered in schizophrenia. This model, presented as a cir­ ing the potential etiological and pathophysiological sig­ cuitry diagram in Figure 1, represents an extension and nificance of these apparent alterations in synaptic con­ refinement of one presented in an earlier publication nectivity requires an understanding of which elements (Lewis and Anderson 1995). of DLPFC circuitry are preferentially affected. Given the accumulating evidence that schizophrenia is a neurodevelopmental disorder (Waddington 1993), FUNCTIONAL MATURATION OF one approach for identifying these vulnerable neural el­ DLPFC CIRCUITRY ements involves studies of the normal maturation of the functional architecture of the DLPFC. Indeed, one of the In both monkeys and humans, the functional matura­ characteristics of schizophrenia is the tendency for clin­ tion of the DLPFC appears to be quite protracted. For ical symptoms to first appear during late adolescence or example, cerebral blood flow in the frontal cortex does early childhood, and it has been suggested that any hy­ not reach adult patterns in humans until 15 to 19 years pothesis regarding the pathophysiology of schizophre­ of age (Chugani et al. 1987; Chiron et al. 1992), and nia must account for this age of onset (Feinberg 1982; adult levels of performance on some cognitive tasks Weinberger 1987). Recent findings indicate that the pri­ mediated by the DLPFC are not achieved until after pu­ mary pathological event in at least some cases of schizo­ berty in both monkeys and humans (see later). To­ phrenia may occur during the pre- or perinatal periods gether, these findings suggest that critical changes in (Benes 1991; Murray et al. 1992; Pilowsky et al. 1993), the organization of the DLPFC may be occurring during with the functional consequences of such developmen­ the peripubertal or adolescent period of development. tal disturbances not clearly evident until the affected In this article, peripubertal and adolescent are used inter­ neural networks become fully mature after puberty changeably to refer to the period of development that (Weinberger 1987). In contrast, other investigators have begins just prior to the onset of puberty and concludes proposed that schizophrenia is due to a disturbance in when all features characteristic of adulthood are late developmental processes that occur during adoles­ achieved. Chronologically, the peripubertal or adoles­ cence (Feinberg 1982; Hoffman and Dobscha 1989). Al­ cent period corresponds roughly to the second decade though the available data are inadequate to reject or ac­ of life in humans and to the age range of two to four cept either hypothesis, both converge on a common years in macaque monkeys. As will become evident in view that late developmental processes are critical to the following sections, the relatively small numbers of the pathogenesis of schizophrenia. both monkey and human subjects that have been in­ Interestingly, studies in both humans and nonhu­ cluded in most studies conducted to date preclude the man primates indicate that the DLPFC does not become identification of more precise epochs within this inter­ functionally mature until after puberty. Consequently, val of development. understanding how the neural circuitry of the DLPFC is One of the cardinal behaviors subserved by the refined during adolescence may provide insights into DLPFC in adults is the performance of delayed-response which elements of this circuitry are disrupted in schizo­ tasks (Fuster 1989). These tasks, some versions of which phrenia. Although the average age of first hospitaliza­ can be performed by both monkeys and humans, re­ tion for schizophrenic patients is in the early or mid­ quire the subject briefly to retain knowledge of the in­ twenties for males and females, respectively (Castle and formation provided by a sensory cue in order to produce Murray 1991; Szymanski et al. 1995), psychotic symp­ the appropriate behavioral response following the re­ toms may appear months or even years prior to hospi­ moval of that cue. For example, in oculomotor delayed­ talization (Haas and Sweeney 1992; Larsen et al. 1996; response tasks, subjects are required to hold "on line" Szymanski et al. 1995). In addition, deterioration in or in "working memory" the location of a visual stimu­ other areas that may be more directly dependent on the lus in space during a delay period when the stimulus is functional integrity of the DLPFC, such as scholastic absent (Goldman-Rakic 1987a). The ability to carry out performance
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