Cortical thickness reduction and volume loss is seen in individuals with schizophrenia before the onset of full clinical illness.Neuronal density is also different from normal brain.It is possible that faulty neuronal migration is the reason behind this. Genetic studies suggest DISC1 (disrupted in schizophrenia 1), RELN (reelin), and NRG1 (neuregulin) ( all important in neuronal migration) are altered in schizophrenia.
Cell migration requires appropriate cell adhesion. Alterations in cell adhesion pathways could be potential contributors to altered neurodevelopment in schizophrenia. Focal adhesion kinase (FAK) signaling pathway regulates the formation of focal adhesions (holding the cell onto the extracellular matrix) and the formation of actin stress fibers (providing the internal tension to drive cell morphology and migration).
Yongjun Fan et al investigated whether olfactory mucosal cells from schizophrenia patients have altered cell adhesion, cell motility, and focal adhesion dynamics. They used olfactory mucosal cells as this mucosa contains multipotent stem cells and are capable of continuing neurogenesis of sensory neurons throughout adult life .
Cultured olfactory neural cells derived from tissue from patients diagnosed with schizophrenia were less adhesive and moved faster than cells derived from people without a psychiatric diagnosis.Patient-derived cells had fewer, smaller, and more dynamic points of attachment to the extracellular substrate and their motility was reduced by inhibition of molecules that regulate attachment to the substrate (Inhibition of FAK and Integrin Binding).There were no significant associations between chlorpromazine equivalents and any of the migration- related outcomes .The observed deficits in this study appear to be intrinsic to the studied cells. However, one has to remember that in the developing brain there would be homeostatic regulation at the cellular, network, and systems levels that is absent in vitro experiments like this.
Focal adhesion kinase could be seen as a molecular hub representing a convergence point in a network of many genes. Multiple gene pathways might be responsible for the biological end point of ‘cell adhesion’. The genetic deficit might be different in each person, but due to converging molecular pathways the end result is same: a deficit in focal adhesion with a result in altered migration pattern.
Conclusion: FAK signaling as a potential candidate pathway that could affect neuronal migration in the developing brain in schizophrenia.
Summary of the article:
Fan Y, Abrahamsen G, Mills R, Calderón CC, Tee JY, Leyton L, Murrell W, Cooper-White J, McGrath JJ, Mackay-Sim A. Biol Psychiatry. 2013 Sep 15;74(6):418-26.