Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

Findings suggest robust olfactory deficits in schizophrenia and at-risk youths. In schizophrenia, several variables had significant impact on these deficits and warrant consideration in prospective studies. Our findings also indicate that olfactory measures may be a useful marker of schizophrenia risk status.

Background Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-Methyl-D-Aspartate Receptor (NMDAR)-mediated inhibition from parvalbumin (PV) interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. Methods In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neurons specific NMDA-R1 knocked-out mice. Results The mice displayed increased baseline gamma power as well as socio-cognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increase neuronal excitability. Conclusions Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological and behavioral changes related to SZ.

The birth and differentiation of neurons have been extensively studied in the olfactory epithelium (OE) of rodents but not in humans. The goal of this study was to characterize cellular composition and molecular expression of human OE in vivo and in vitro. In rodent OE, there are horizontal basal cells and globose basal cells that are morphologically and functionally distinct. In human OE, however, there appears to be no morphological distinction among basal cells, with almost all cells having round cell bodies similar to rodent globose basal cells. Unlike the case in rodents, human basal cells, including putative neuronal precursors, express p75NGFR, suggesting a distinctive role for p75NGFR in human OE neurogenesis. Molecular expression of neuronal cells during differentiation in human OE grossly follows that in rodents. However, the topographical organization of immature and mature ORNs in human OE differs from that of rodents, in that immature and mature ORNs in humans are dispersed throughout the OE, whereas rodent counterparts have a highly laminar organization. These observations together suggest that the birth and differentiation of neuronal cells in human OE differ from those in rodents. In OE explant culture, neuronal cells derived from human OE biopsy express markers for immature and mature neurons, grossly recapitulating neuronal differentiation of olfactory neurons in vivo. Furthermore, small numbers of cells are doubly label for bromodeoxyuridine and olfactory marker protein, indicating that neuronal cells born in vitro reach maturity. These data highlight species-related differences in OE development and demonstrate the utility of explant culture for experimental studies of human neuronal development.

Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system-owing to its strategic anatomic location-may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an "early warning" sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.