In schizophrenia, hippocampal perfusion is increased and declarative memory function is degraded. Based on a model of hippocampal dysfunction in schizophrenic psychosis, we postulated increased NMDA receptor signaling in CA3. Here we demonstrate that the GluN2B-containing NMDA receptors (GluN2B/GluN1) and its associated postsynaptic membrane protein PSD95 are both increased in human hippocampal CA3 from schizophrenia cases, but not in CA1 tissue. Quantitative analyses of Golgi-stained hippocampal neurons show an increase in spine density on CA3 pyramidal cell apical dendrites (stratum radiatum) and an increase in the number of thorny excrescences. AMPA receptor subunit proteins are not altered in CA3 or CA1 subfields, nor are several additional related signaling proteins. These hippocampal data are consistent with increased excitatory signaling in CA3 and/or with an elevation in silent synapses in CA3, a state which may contribute to development of long term potentiation with subsequent stimulation and ‘un-silencing’. These changes are plausibly associated with increased associational activity in CA3, degraded declarative memory function and with psychotic manifestations in schizophrenia. The influence of these hyperactive hippocampal projections onto targets in limbic neocortex could contribute to components of schizophrenia manifestations in other cerebral regions.

Reduction of volume and neuronal number has been found in several association nuclei of the thalamus in schizophrenic subjects. Recent evidence suggests that schizophrenic patients exhibit abnormalities in early visual processing and that many of the observed perceptual deficits are consistent with dysfunction of the magnocellular pathway, i.e. the visual relay from peripheral retinal cells to the two ventrally located magnocellular layers of the lateral geniculate nucleus (LGN). The present study was undertaken to determine whether abnormalities in cell number and volume of the LGN are associated with schizophrenia and whether the structural alterations are restricted to either the magnocellular or parvocellular subdivisions of the LGN. Series of Nissl-stained sections spanning the LGN were obtained from 15 schizophrenic and 15 normal control subjects. The optical disector/ fractionator sampling method was used to estimate total neuronal number, total glial number and volume of the magnocellular and parvocellular subdivisions of the LGN. Cell number and volume of the LGN in schizophrenic subjects were not abnormal. Volume of both parvocellular and magnocellular layers of the LGN decreased with age. These findings do not support the hypothesis that early visual processing deficits are due to reduction of neuronal number in the LGN.

Prenatal exposure of the brain to environmental insult causes different neurological symptoms and behavioral outcomes depending on the time of exposure. To examine the cellular bases for these differences, we exposed Rhesus macaque fetuses to x-rays during early gestation (E30–E42), i.e., before the onset of corticogenesis, or in midgestation (E70–E81) when superficial cortical layers are generated. Animals were delivered at term (~E165), and the size and cellular composition of prefrontal association cortex (area 46) examined in adults, using magnetic resonance imaging (MRI) and stereologic analysis. Both early and midgestational radiation exposure diminished the surface area and volume of area 46. However, early exposure spared cortical thickness and did not alter laminar composition, and due to higher cell density, neuron number was within the normal range. In contrast, exposure to x-rays at midgestation reduced cortical thickness, mainly due to elimination of neurons destined for the superficial layers. A cell-sparse gap, observed within layer III, was not filled by the later generated neurons destined for layer II, indicating that there is no subsequent replacement of the lost neurons. The distinct areal and laminar pathology consequent to temporally segregated irradiation is consistent with basic postulates of the radial unit hypothesis of cortical development. In addition, we show that an environmental disturbance inflicted in early gestation can induce subtle cytoarchitectonic alterations without loss of neurons, such as those observed in schizophrenia, whereas midgestational exposure causes selective elimination of neurons and cortical thinning as observed in some forms of mental retardation and fetal alcohol syndrome.

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3 1 2 years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.3877.65 mm in AMPH-sensitized compared to 162.9877.26 mm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia. Neuropsychopharmacology (2007) 32, 919-931.

Neurons in the macaque brain arise from progenitors located near the cerebral ventricles in a temporally segregated manner such that lethal doses of ionizing irradiation, if administered over a discrete time interval, can deplete individual nuclei selectively. A previous study showed that neuron number in the dorsal lateral geniculate nucleus is reduced following early gestational exposure to x-irradiation (Algan and Rakic, 1997). Here we examine whether similarly timed irradiation decreases neuron number in three associational thalamic nuclei: mediodorsal (MD), anterior, and pulvinar. Ten macaques were exposed to multiple doses of x-rays (total exposure: 175-350cGy) in early (E33-E42) or midgestation (E70-E90); 8 non-irradiated macaques were controls. Only the early irradiated monkeys, not the midgestationally irradiated animals, exhibited deficits in whole thalamic neuron (−15%) and glia numbers (−21%) compared to controls. Reduction of neuron number (−26%) and volume (−29%) was particularly pronounced in MD. In contrast, cell number and volume were not significantly decreased in the anterior or pulvinar nuclei following early gestational irradiation. Thus, reduced thalamic neuron number was associated specifically with irradiation in early gestation. Persistence of the thalamic neuronal deficit in adult animals indicates that prenatally deleted neurons had not been replenished during maturation or in adulthood. The selective reduction of MD neuron number also supports the protomap hypothesis that neurons of each thalamic nucleus originate sequentially from separate lines of neuronal stem cells (Rakic, 1977a). The early gestationally irradiated macaque is discussed as a potentially useful model for studying the neurodevelopmental pathogenesis of schizophrenia. Keywordsanterior nucleus; pulvinar nucleus; neurodevelopment; stereology; schizophrenia Systematic studies, based on injections of tritiated thymidine into pregnant macaque monkeys at different gestational ages, have established that each population of neurons in the developing primate brain is born, i.e., undergoes final mitotic division of the progenitor cells, during a specific and limited period (e.g. Rakic, 1974Rakic, , 2002. For example, neurons destined to become the thalamus are born during the first trimester of pregnancy with neurogenesis in the dorsal lateral geniculate nucleus (dLGN) (E36-E43) having a similar although less prolonged duration than that of the pulvinar nucleus (E36-E45) (Rakic, 1977a; Correspondence: Lynn D. Selemon, Ph.D., Department of Neurobiology, Yale University School of Medicine, PO Box 208001, New Haven, CT, 06520-8001, phone: 508-540-5306, fax: 508 540-5306, e-mail: ldselemon@aol.com Ogren and Rakic, 1981). Neurogenesis in many other subcortical structures including the neostriatum (E36-E80), nucleus accumbens (E36-E85), septal nuclei (E36-E62), basal cholinergic nuclei (E33-E48), and brain stem monoaminergic nuclei (E27-E43), begins in early gestation and overlaps with thalamogenesis Rakic, 1979, 1980;L...