Neurodevelopmental hypothesis of schizophrenia: a central sensory disturbance

Medical Hypotheses (2000) 55(4), 314–318 © 2000 Harcourt Publishers Ltd doi: 10.1054/mehy.2000.1059, available online at http://www.idealibrary.com on

Neurodevelopmental hypothesis of schizophrenia: a central sensory disturbance T. Lafargue, J. Brasic Department of Psychiatry, New York University Medical Center, Bellevue Hospital, Comprehensive Psychiatric Emergency Program, New York, USA

Summary Schizophrenia is a syndrome that is believed to have its onset during very early corticogenesis of the affected patient. The subsequent structural and functional cerebral variations observed in people with schizophrenia suggest an altered overall pattern of brain morphology. The alterations in cerebral structure and function in schizophrenia suggest that an early disturbance of the central nervous sensory modality may be occurring in the patient. Placing the structural and functional cerebral deficits reported in schizophrenia within the context of normal brain structure and function provides a neurological basis to identify early pathological molecular mechanisms and programs that may be resulting in schizophrenia. © 2000 Harcourt Publishers Ltd

INTRODUCTION This article reviews the reported deviations of cerebral structure and function in schizophrenic patients within the context of a healthy central nervous system (CNS) development (1–9), organization (10–13), and physiology (14–17). A compendium of the transient telencephalic structures of very early corticogenesis will be presented. The early cortical activities of the cooperating neuromodulating systems of excitation (i.e. glutamatergic) and inhibition (i.e. γ-amino butyric acid (GABAergic) will be addressed. The relationship of the first developing guide neurons (i.e. ‘pioneer neurons’) and the phenomenon of long-term potentiation (LTP) to the structuring and stabilization of cortical and subcortical circuits will be discussed. Finally, after briefly summarizing corticogenesis, synaptic stabilization, and the actions of the mediating

Received 20 December 1999 Accepted 25 January 2000 Correspondence to: Todd Lafargue MD, Department of Psychiatry, New York University Medical Center, Bellevue Hospital, Comprehensive Psychiatric Emergency Program, 462 1st Avenue, New York, NY 10016, USA. Phone: + 1 212 562 4330; Fax + 1 212 562 4447

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neuromodulators; we will consider faulty processes that may be underlying the brain variations reported in schizophrenia. THE DEFINITION OF SCHIZOPHRENIA The term, schizophrenia, applies to a chronic neurological syndrome usually manifesting during late adolescence or early adulthood. Schizophrenia is a dysjunctive diagnostic category (18) characterized by a patient population remarkable for an array of differing and often overlapping signs and symptoms (e.g. hallucinations, delusions, thought disorder, poverty of thought/action, flat affect) (19–22). The phenomenology of schizophrenia has most logically been typed as either positive (type 1) or negative (type 2) (21) depending on observability. Factor analysis distinguishes three statistical profiles (i.e. disorganization, psychosis, and negative symptom) (23,24). The documented similarities between clinical schizophrenia and other neuropsychiatric disorders including temporal lobe epilepsy, the dementias, and frontal lobe syndrome provide a context for studying cerebral structure and function in schizophrenia (25–27). Data from postmortem, imaging, epidemiological, physiological, neurochemical, and preclinical research consistently indicate that

Neurodevelopmental hypothesis of schizophrenia

schizophrenia is the consequence of a neurodevelopmental disorder which may include neurodegenerative aspects. BRAIN STRUCTURE IN SCHIZOPHRENIA Structural in vivo neuroimaging and neuropathological studies have reported variations in a wide range of cranial, cortical, and subcortical structures in schizophrenic patients compared to healthy controls (28,29). Neuroimaging studies consistently characterize reductions in patients’ total brain and intracranial size (30) and enlargement of the third and lateral ventricles and cortical sulci (29,31,32). Postmortem cytoarchitectural studies report abnormal cortical and subcortical neuronal size, number, and position in the brains of schizophrenic patients (33). Interestingly, a pattern of cerebral pathology consistent with a centripetally displaced laminar architecture has also been demonstrated (29). BRAIN FUNCTION IN SCHIZOPHRENIA Neuropsychological and functional imaging studies suggest the structural deficits in schizophrenia reflect a ‘dysconnectedness’ of temporolimbic–prefrontal cerebral circuitry. The dysconnected circuitry is believed to underlie the organizational and memory deficits routinely observed in schizophrenic patients (29). Evidence suggests that not only regional cerebral circuitry is dysconnected, but more localizable sensory circuit maldevelopment may be occurring in the brains of schizophrenic patients. Backward masking and event-related potential (ERP) studies, assessing initial visual and auditory sensory integration, suggest that functional deficits may be traced to early sensory information processing occurring within the millisecond time frame (34,35). These findings suggest a malfunction is occurring with the connections comprising the neuronal systems responsible for the very early stages of sensory processing. Such a sensory system failure may contribute to the hallucinations, delusions, and thought disorders observed in patients with schizophrenia (34). THE RELATIONSHIP OF SCHIZOPHRENIA TO EARLY NEURODEVELOPMENT Research suggests that schizophrenia may result from a neurodevelopmental variation, possibly occurring during the second trimester of human gestation (36). In all primates, the first half of gestation represents the period during which the developing embryo produces its entire complement of cortical neurons (11). Accordingly, a satisfactory appreciation of early corticogenesis and the neuromodulating agents allowing this process to take © 2000 Harcourt Publishers Ltd

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place helps to further illuminate the clinical correlations of schizophrenia to its underlying brain architecture and electrophysiology.

CORTICOGENESIS The initial phase of corticogenesis Studies have demonstrated that cortical cells are generated from the neuroepithelium (i.e. the proliferative, ventricular zone) of the telencephalic vesicle during the first half of gestation in primates (9,11). The initial postmitotic neurons form the primordial plexiform layer (1) or preplate (9,37). The preplate assumes a position superficial to the neuroepithelium, and lies immediately beneath the pial surface. These initial cells are morphologically distinct from the later generated cortical cells that will comprise the second through sixth laminations in the adult brain (6,7,10). The preplate undergoes differentiation independent of afferent influence. It is split into a superficial, marginal zone and a deep, subplate zone. This split occurs by the increasing presence of postmitotic cortical plate cells that are actively migrating from the proliferative zone into the area occupied by the preplate (9). During postnatal life, the superficial, marginal zone becomes cortical layer 1; the cortical plate expands, and is horizontally constructed into laminations 2–6 following an inside-out developmental gradient; the subplate largely undergoes programmed cell death. Notably, a fraction of subplate neurons are found surviving in the adult brain as interstitial neurons of the white matter (10,38). Studies by Akbarian (39–42) suggest that schizophrenic patients may have abnormal interstitial neurons of the white matter. This finding implicates a possible disturbance of subplate zone function as a cause for the future development of schizophrenia in the offspring. This information provides a basis for taking a closer look at the molecular events taking place at the subplate zone during very early corticogenesis. The subplate zone The subplate represents a zone of transient tissue hypothesized (43) to play a major role in the structural and functional development of cortical and subcortical systems (6–9). The subplate zone gives rise to ‘pioneer’ (5–7) neurons. These neurons lay down the first axons that subsequent ascending and descending neurons follow as guidelines in properly establishing their central and peripheral connections. Pioneer neurons are necessary for the later generated projection neurons from deeper cortical layers to distinguish and invade their proper subcortical targets. The subplate zone is required Medical Hypotheses (2000) 55(4), 314–318

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for area-specific cortex targeting and ingrowth of ascending thalamocortical afferent, projection neurons (6–9,44). The neuromodulators present at the subplate zone and long-term potentiation During early neurodevelopment, the subplate zone is the site of high concentrations of the neurotransmitter γ-amino butyric acid (GABA). GABA acts in an inhibitory capacity (9,12,45), and possibly functions as a trophic factor during normal neurodevelopment (46–48). GABA inhibition at the subplate zone occurs before the ‘classic’ inhibitory interneurons (e.g. chandelier, basket, and horsetail cells) have become fully differentiated. Wahle and Meyer (45) emphasize that GABA’s early expression and strong inhibitory influence occur when subplate neurons are relatively mature compared to the development stages of other local neuronal circuits of the cortical plate (46). Thus, GABA may protect the immature cortex from overexcitation from morphologically more mature excitatory systems (45,49). Indeed, evidence suggests that excitation of the developing cortical plate cells by glutamatergic afferent neural mechanisms may be harmful to the cortical plate cells if GABAergic inhibition is hypoactive (12). Of particular significance to the syndrome of schizophrenia, Luhmann and Prince state, ‘the relative ineffecacy of GABAergic inhibition in juvenile cortex promotes the expression of NMDA receptor-mediated activity at this age, which in turn, may play a role in developmental plasticity and increased seizure susceptibility of immature cortex’ (50). The similarities between seizure states and symptomatic schizophrenia have been reported on by several authorities (22,27). In conjunction with GABAergic functions at the subplate zone, the excitatory input of the N-methyl-Daspartate (NMDA) type of glutamate receptor is another principle component allowing for the proper structuring and stabilization of developing neuronal contacts during corticogenesis (17). Interestingly, the NMDA receptor mediates neuronal growth in a like manner in cellularly disparate brain regions (e.g. the hippocampus and the visual cortex) (51). NMDA mechanisms are believed to participate in the structuring of cortical sensory, motor, and limbic systems by performing the synaptic phenomenon of LTP. Long-term potentiation LTP, first described in the rabbit hippocampal formation (15), is a rapid and persistent enhancement of synaptic efficacy (52). One of the functional cerebral effects of LTP is the synaptic stabilization of memory and learning circuits (14,15). The molecular mechanisms related to Medical Hypotheses (2000) 55(4), 314–318

activity-dependent NMDA responses underly the synaptic phenomenon of LTP (15–17). Importantly, and worthy of emphasis, LTP occurs in numerous, cellularly distinct, and activity-specific groups of the developing cerebral neurons (i.e. prefrontal, cingulate, striatal, motor, visual, and hippocampal cortices) (51,53). A defective LTP mechanism during early neuronal development may lead to the future deficits observed in schizophrenic patient’s working memory function. GABA, NMDA receptors, and calcium The preceding discussion suggests that inhibition and excitation exerted by the GABAergic and glutamatergic systems, respectively, are necessary for proper neurodevelopment. The inhibitory and excitatory functions of GABA and glutamate appear to cooperatively facilitate the proper cerebral development of histologically varying regions. Calcium (Ca++) has been reported as the excitatory ion under the regulation of the GABA and glutamate in stimulating neuronal growth or death in the developing and varying brain regions of the human being (54–56). CONCLUSION The above discussion provides a neural basis for conjecture regarding the possible ionic and cellular mechanisms potentially malfunctioning during early corticogenesis in schizophrenia. Possibly, an insult or injury to the mechanisms of GABAergic and/or glutamatergic influence at the subplate zone during early corticogenesis may largely contribute to the later manifestation of clinical schizophrenia. Malfunction of the cooperating sensory systems of excitation and inhibition at the subplate zone would result in the failure of pioneer neurons to properly differentiate and migrate to their proper cerebral locations. Consequently, the later migrating projection neurons may fail to reach or invade their preselected area-specific brain sites. In addition to the possibility of an initial sensory abnormality occurring at the subplate zone; GABAergic and glutamatergic dysfunction may be occurring during the later development of cortical laminations 1–6. Required for normal cortical development is the proper differentiation and stabilization of area-specific synaptic contacts via the excitatory and inhibitory neuromodulation of LTP mechanisms (i.e. NMDA receptor functions). If the NMDA receptor is antagonized in healthy controls, a psychosis usually occurs in the patient (57). A disturbance of the proper GABAergic and glutamatergic influences would upset NMDA mechanisms and normal cortical development. If such a disturbance is actively occurring from the onset of cerebral ontogeny, the © 2000 Harcourt Publishers Ltd

Neurodevelopmental hypothesis of schizophrenia

affected individual may suffer from the signs and symptoms observed in schizophrenia. The timing of illness onset remains puzzling, however, the usual onset of clinical schizophrenia approximates the normal, age-related termination of white matter growth in adulthood (58).

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