Neural stem cell proliferation is decreased in schizophrenia, but not in depression

Abstract

The phenomenon of adult neurogenesis (AN), that is, the generation of functional neurons from neural stem cells in the dentate gyrus of the hippocampus, has attracted remarkable attention, especially as it was shown that this process is also active in the human brain. Based on animal studies, it has been suggested that reduced AN is implicated in the etiopathology of psychiatric disorders, and that stimulation of AN contributes to the mechanism of action of antidepressant therapies. As data from human post-mortem brain are still lacking, we investigated whether the first step of AN, that is, the level of neural stem cell proliferation (NSP; as quantified by Ki-67 immunohistochemistry), is altered in tissue from the Stanley Foundation Neuropathology Consortium comprising brain specimens from patients with bipolar affective disorder, major depression, schizophrenia as well as control subjects (n = 15 in each group). The hypothesis was that stem cell proliferation is reduced in affective disorders, and that antidepressant treatment increases NSP. Neither age, brain weight or pH, brain hemisphere investigated nor duration of storage had an effect on NSP. Only in bipolar disorder, postmortem interval was a significant intervening variable. In disease, onset of the disorder and its duration likewise did not affect NSP. Also, cumulative lifetime dose of fluphenazine was not correlated with NSP, and presence of antidepressant treatment did not result in an increase of NSP. Concerning the different diagnostic entities, reduced amounts of newly formed cells were found in schizophrenia, but not in major depression. Our findings suggest that reduced NSP may contribute to the pathogenesis of schizophrenia, whereas the rate of NSP does not seem to be critical to the etiopathology of affective disorders, nor is it modified by antidepressant drug treatment.

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

“…LIS1, DISC1 and nuclear distribution protein nudE-like 1 (NDEL1) have been shown to be part of a molecular interaction complex relevant in neurodevelopment [55][56][57][58] . Morphological changes in DISC1 mice have been observed including reduced prefrontal cortex volume and impaired growth and dendritic orientation in the dentate gyrus, correlating with findings in human schizophrenia studies [59][60][61] .…”

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

“…Clearly, the most direct approach to test this theory is the examination of dentate neurogenesis in depressed patients. So far, there is only one study published recently by Reif et al (2006), which compared the level of neural stem cell proliferation in post mortem hippocampal samples from patients with major depression, bipolar affective disorder and schizophrenia. The authors did not find any evidence of suppressed neurogenesis in the dentate gyri of depressed patients.…”

Neurogenic hypothesis and psychiatric disorders

“…A clinical study which used post-mortem brain sections of major depressive patients showed no significant difference in the number of hippocampal proliferating cells between normal controls and depressive patients [26]. However, due to experimental limitation in using human tissues, several aspects should be noted.…”

“…According to a post-mortem study conducted by Reif et al [26], the density of Ki-67 (a nuclear antigen expressed by proliferative cells) in the dentate gyrus of schizophrenia patients was 60% lower than that of control subjects. Surprisingly samples from bipolar disorder and major depression patients did not show a significant lower cell density than the controls.…”

“…Though some other controversial results have also shown, these results have given the possible relationship between the morphological changes of the amygdala and the pathophysiologic development of autism. Mercadante et al [99] [110,111] Growth factors: 1) Brain-derived neurotrophic factor (BDNF) [31] 2) Vascular endothelial growth factor (VEGF) [41] 3) Insulin-like growth factor 1 (IGF1) [41] Neurotransmitters: 1) GABA [36] 2) Serotonin [37] 3) Glutamate/NMDA receptor [38] 4) Dopamine and acetylcholine [39] -Decrease in number of Ki-67 +ve cells in schizophrenia patients [26] Intracellular molecules: 1) Disrupted in Schizophrenia 1 (DISC1) [75] 2) Neuronal PAS domain protein 3 (NPAS3) [85] 3) Neuregulin 1 (NRG1) [ [99,103] have further suggested that the new immature-neurons newly produced in the amygdala may be helpful in increasing the ability to learn from new experiences via modulation of the gamma-aminobutyric acid (GABA) as patients with autism were found to have alteration on the GABAergic system. However, further investigations are needed as this is a new etiologic hypothesis of autism.…”