Evidence-Based Reviews

Do neural disconnects cause schizophrenia?

Current Psychiatry. 2007 May;6(5):90-96

References

1. Gogtay N, Sporn A, Rapoport J. Structural brain MRI studies in childhood-onset schizophrenia and childhood atypical psychosis. In: Lawrie S, Johnstone E, Weinberger D, eds. Schizophrenia: from neuroimaging to neuroscience. New York, NY: Oxford University Press; 2004.

2. Higgins ES, George MS. The neuroscience of clinical psychiatry. Philadelphia: Lippincott, Williams, and Wilkins; 2007.

3. Selemon LD. Increased cortical neuronal density in schizophrenia. Am J Psychiatry 2004;161(9):1564.-

4. Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000;57(1):65-73.

5. Csernansky JG. Neurodegeneration in schizophrenia: evidence from in vivo neuroimaging studies. Scientific World Journal 2007;7:135-43.

6. Kubicki M, McCarley R, Westin CF, et al. A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res 2007;41(1-2):15-30.

7. Hof PR, Haroutunian V, Friedrich VL, Jr, et al. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003;53(12):1075-85.

8. Hakak Y, Walker JR, Li C, et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001;98(8):4746-51.

9. Shih RA, Belmonte PL, Zandi PP. A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatr 2004;16(4):260-83.

10. McClellan JM, Susser E, King MC. Maternal famine, de novo mutations, and schizophrenia. JAMA 2006;296(5):582-4.

11. Limosin F, Rouillon F, Payan C, et al. Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand 2003;107(5):331-5.

12. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002;159(7):1080-92.

13. Pedersen CB, Mortensen PB. Urbanization and traffic related exposures as risk factors for schizophrenia. BMC Psychiatry 2006;6:2.-

14. Arendt M, Rosenberg R, Foldager L, et al. Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Br J Psychiatry 2005;187:510-5.

15. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genetics 2003;33(suppl):245-54.

16. Abdolmaleky HM, Smith CL, Faraone SV, et al. Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. Am J Med Genet B Neuropsychiatr Genet 2004;127(1):51-9.

17. Fatemi SH, Stary JM, Earle JA, et al. GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr Res 2005;72(2-3):109-22.

18. Abdolmaleky HM, Cheng KH, Russo A, et al. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 2005;134(1):60-6.

19. Grayson DR, Jia X, Chen Y, et al. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci USA 2005;102(26):9341-6.

20. McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry 2006;163(5):790-799.

21. Dierks T, Linden DE, Jandl M, et al. Activation of Heschl’s gyrus during auditory hallucinations. Neuron 1999;22(3):615-21.

22. Hubl D, Koenig T, Strik W, et al. Pathways that make voices: white matter changes in auditory hallucinations. Arch Gen Psychiatry 2004;61(7):658-68.

Adapted from The neuroscience of clinical psychiatry, by Edmund S. Higgins and Mark S. George. Philadelphia: Lippincott, Williams, and Wilkins; 2007:251-63.

Figure 3 Reduced neuron myelination possible in schizophrenia

In a postmortem analysis, stained white matter sections taken from schizophrenia patients had fewer oligodendrocytes, cells that insulate axons with myelin and facilitate electrical transmission.

Source: Adapted from reference 2

Genes and the environment

Schizophrenia’s heritability is among the most repeated research findings in psychiatry.⁹ Other mechanisms besides genetics must be involved, however, as studies consistently show that monozygotic twins have a concordance rate of approximately 50% for the development of schizophrenia.

Clinical Point

Lowered production of proteins such as reelin may reduce connections between neurons and cause schizophrenia symptoms

Environmental factors. Adverse environmental events may act in conjuction with genetic predisposition to trigger schizophrenia development. Ischemia or an impoverished diet, for example, have the potential to change DNA methylation.

Environmental factors associated with increased risk for schizophrenia include:

maternal starvation during pregnancy¹⁰
prenatal exposure to influenza¹¹
obstetrical complications with hypoxia¹²
being born and raised in an urban environment¹³
using marijuana during adolescence.¹⁴

Gene expression. Important genes may be silenced in individuals with increased DNA methylation and a susceptible genetic profile. Alterations in gene expression are the fundamental mechanism of behavioral change. Research shows that environmental events can alter gene expression without changing the genetic code, such as by adding methyl groups to DNA.^15,16 The silencing of important developmental genes in this way can have devastating effects on development.

Clinical Point

Auditory hallucinations originate from altered connectivity in the same regions that process normal hearing and speech

One explanation for the development of schizophrenia is that environmental events in susceptible individuals silence the production of proteins essential for maintaining neuronal connections through methylation of DNA. Postmortem analysis of brains of patients with schizophrenia show reduced mRNA of reelin,¹⁷ a protein produced in gamma-aminobutyric acid neurons involved in neuronal migration, axon branching, and synapse formation during brain development. Lowered production of proteins such as reelin may reduce connections between neurons and cause schizophrenia symptoms. Two research groups also have reported increased methylation of reelin DNA in postmortem studies of the brains of patients with schizophrenia.^18,19 Increased methylation of DNA would silence production of this important protein.

Preventing neural disconnects? If schizophrenia is a developmental disorder resulting from failures in brain connectivity, then the ultimate treatment may be prevention. Recent research suggests that intervening with second-generation antipsychotics during the prodromal stage can prevent or delay the emergence of the disorder.²⁰ Further research is needed to establish whether early intervention can prevent schizophrenia’s neuronal disruption.