Collectively, these research findings provide compelling evidence that schizophrenia patients exhibit structural and functional abnormalities of the olfactory system that extend from the cortex to the periphery. The presence of olfactory deficits in unaffected first-degree relatives of patients implicates, at least in part, a genetic etiology. Similarly, the presence of structural abnormalities associated with midline craniofacial and forebrain morphogenesis implicates an early embryonic developmental etiology. Importantly, there is an emerging pattern of relative dissociation between these genetic and developmental markers. Individuals who carry an increased genetic risk have functional olfactory deficits, as indicated by behavioral and electrophysiological measures. However, they do not exhibit the structural abnormalities that are most indicative of an early gestational disturbance (ie, reduced nasal cavity volume and shallow olfactory sulcus). Although data regarding other minor physical anomalies are somewhat contradictory,118–122
these olfactory findings are in agreement with studies indicating that physical anomalies can distinguish monozygotic twins discordant for schizophrenia,120
are prominent in sporadic but not familial schizophrenia,120
and are not found in unaffected family members.121,122
It thus appears that structural and functional deficits may represent 2 relatively independent sets of measures that can be used to track, respectively, intrauterine environmental and genetic contributions to schizophrenia vulnerability. Of course, this dissociation is not absolute and this is not to suggest that genetic factors do not contribute to morphological abnormalities. Rather, it suggests that these structural measures may be especially sensitive to the environmental factors that influence embryonic development, while functional olfactory deficits may be more sensitive endophenotypic markers of an underlying genetic vulnerability.
This has important implications for the use of these measures as potential biomarkers, particularly in the context of longitudinal studies of individuals who are either at genetic risk due to a family history of schizophrenia or exhibiting behavioral changes consistent with a schizophrenia prodrome. As noted above, olfactory identification impairments predicted subsequent conversion to schizophrenia among “ultra–high-risk” individuals who either were exhibiting subthreshold psychotic symptoms or had a family history of psychosis and a significant decline in functioning.49
While it still remains to be demonstrated, a composite measure that incorporates both structural and functional elements would presumably have greater sensitivity and specificity for predicting schizophrenia in this case than a functional measure alone. Also, the ultra–high-risk research strategy does not address the question of how to identify, prior to the onset of prodromal symptoms, those individuals with a family history of schizophrenia that are likely to develop the illness. In this case, the presence of both structural and functional olfactory abnormalities may be a critical distinguishing feature. Future longitudinal studies, therefore, should include the concurrent assessment of both sets of measures.
Although we cannot, at this point, identify the specific mechanisms that underlie these olfactory impairments, we can speculate about some of the broader processes that may be involved. Developmental abnormalities in midline craniofacial and forebrain morphogenesis suggest a disturbance in the cell-cell signaling mechanisms that regulate embryonic mesenchymal/epithelial tissue interactions.123
Mesenchymal/epithelial induction during the first trimester of embryogenesis gives rise to the entire frontonasal region, including the olfactory epithelium, OB and rudimentary forebrain.124
This set of complex tissue interactions is regulated by a group of molecules (including retinoic acid, sonic hedgehog, Notch4, and FGF) that control gene expression, and any dysregulation of this process could produce minor anomalies. Among these regulatory molecules, retinoic acid may be of particular interest. Retinoids have been previously implicated in the pathophysiology of schizophrenia125,126
and vitamin A deficiency is a prenatal nutritional factor that both increases the risk of illness and produces congenital malformations that resemble the stigmata of schizophrenia.127
Importantly, retinoic acid also regulates the expression of multiple schizophrenia candidate genes and target molecules, including dysbindin,128
dopamine and dopamine receptors, NMDA receptors, nicotine receptors, GABA receptors,129
and elements of the G-protein—cAMP—protein kinase A intracellular signaling pathway.130
The integrity of the olfactory system may also be maintained, in the adult brain, by retinoic acid-mediated regulation of neurogenesis.131
It remains to be determined whether retinoids are specifically implicated in the etiology of schizophrenia olfactory deficits. We would emphasize, though, that an epigenetic regulatory mechanism of this sort offers a plausible unifying explanation for this multitiered array of structural, functional, genetic, developmental, inter-, and intracellular abnormalities. We would also note, in this context, that there is a growing appreciation of the potential importance of epigenetic mechanisms in the pathophysiology of schizophrenia.132