Cognitive Disorders: Schizophrenia

• Schizophrenia is a life long psychiatric disorder that often strikes in the late teens or early twenties. 

• There is strong genetic component that is also significantly shaped by environmental  factors. 

• The disease often involves excessive loss of gray matter (Cannon TD, et al. (2002) Cortex mapping reveals regionally specific patterns of genetic and disease- specific gray-matter deficits in twins discordant for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99:3228–32332) (Cannon TD et al.,(2015) Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk.  Biol Psychiatry Jan 15;77(2):147-57. doi: 10.1016/j.biopsych.2014.05.023) and reduced numbers of synaptic structures on neurons, (Garey LJ, et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry. 1998; 65:446–453). 

• Schizophrenia is associated with decreased dendritic spine density on prefrontal cortical pyramidal neurons  (Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013; 251:90– 107).

• Consequently cognition, memory and  perception are often impaired.

• Psychotic symptoms (positive which are: hallucinations, delusions, thought disorders and paranoia, even movement disorders: negative which are: flat affect, lack or loss of emotion and speech, reduced sense of pleasure, difficultly initiation, maintaining activity)  of schizophrenia are treated medicinally with varying degrees of success. 

• The cause and mechanisms involved with schizophrenia are not well understood. 

• Significant effort has been put forth to understand the genetic basis of schizophrenia.

• More than 100 loci in the human genome contain SNP haplotypes that associate with risk of schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511:421–427). 

• There is an association between schizophrenia and genetic markers across the Major Histocompatibility Complex (MHC) locus. 

• The MHC locus is known for its role in immunity, containing highly polymorphic human leukocyte antigen (HLA) genes that encode many antigen-presenting molecules. Autoimmune diseases may have genetic associations at the MHC locus that arise from alleles of HLA genes. Schizophrenia’s association to the MHC is not yet explained.

• Studies have shown that strongly associated markers are near a complex, multi-allelic, and partially characterized form of genome variation that affects the C4 gene encoding complement component 4. Schizophrenia  is associated to CSMD16,10, which encodes a regulator of C413. (Sekar. et al., (2016) Schizophrenia risk from complex variation of complement component 4 Nature. February 11; 530(7589): 177–183).

• In addition, very recently C5 levels in CSF were abnormally high in several psychiatric disorders, including bipolar disorder and schizophrenia. (Ishii T et al. (2018) Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia.Biochem Biophys Res Commun. Mar 4;497(2):683-688).