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Neurogenesis and schizophrenia: dividing neurons in a divided mind?

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Abstract

Forty years after the initial discovery of neurogenesis in the postnatal brain of the rat, convincing evidence has been accrued that functional neurons are generated throughout the entire lifespan, particularly in the dentate gyrus (DG) and the subventricular zone (SVZ). This phenomenon has been termed adult neurogenesis (AN) and while it was detected in all examined mammalian species including humans, the physiological role of this process remains unknown. Although a plethora of animal studies indicate an involvement of AN in the pathophysiology of depression, this view has recently kindled considerable controversy. Pertinent studies in humans failed to confirm a role of reduced hippocampal neural stem cell proliferation (NSP) in depression but suggest a contribution to the pathophysiology of schizophrenia. The functional relevance of disturbed AN may encompass erroneous temporal encoding of new memory traces, thereby contributing to cognitive deficits observed in schizophrenia. This AN-hypothesis of schizophrenia is supported by neuroimaging, as well as by several genetically modified rodent models, e.g. reelin and NPAS3 knockout mice. Furthermore, several genes impacting on AN, including NPAS3, were also found to be associated with schizophrenia by case-control studies. In conclusion, several lines of evidence suggest that reduced AN may contribute to the etiopathogenesis of schizophrenic disorders, whereas it does not seem to be a critical risk factor for affective disorders.

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Abbreviations

AN:

Adult neurogenesis

BDNF:

Brain derived neurotrophic factor

BrdU:

5-bromo-2-deoxyuridine

DG:

Dentate gyrus

DISC1:

Disrupted in schizophrenia 1

ECT:

Electroconvulsive treatment

FGF-2:

Fibroblast growth factor 2

GCL:

Granule cell layer

NMDA:

N-methyl-D-asparate

NO:

Nitric oxide

NOS-I:

Nitric oxide synthase type I (neuronal)

NOS-III:

Nitric oxide synthase type III (endothelial)

NPAS3:

Neuronal PAS domain protein 3

NSP:

Neural stem cell proliferation

OB:

Olfactory bulb

PCP:

Phencyclidine

PPI:

Pre-pulse startle inhibition

SGZ:

Subgranular zone

SVZ:

Subventricular zone

TLE:

Temporal lobe epilepsy

VEGF:

Vascular endothelial growth factor

Wnt:

Wingless-type MMTV integration site family

Wnt 3:

Wnt member 3

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Correspondence to Andreas Reif.

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The work of the authors is supported by the Deutsche Forschungsgemeinschaft (Grant RE1632/1–1 and 1–3 to A.R., KFO 125/1–1 D to A.R. and K.P.L., and SFB 581 to K.P.L.), BMBF (IZKF 01 KS 9603) and the European Commission (NEWMOOD LSHM-CT-2003-503474).

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Reif, A., Schmitt, A., Fritzen, S. et al. Neurogenesis and schizophrenia: dividing neurons in a divided mind?. Eur Arch Psychiatry Clin Neurosc 257, 290–299 (2007). https://doi.org/10.1007/s00406-007-0733-3

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