Important unanswered questions about adult neurogenesis in schizophrenia

Abstract

Purpose of reviewAberrant neurogenesis may contribute to the pathogenesis, pathophysiology and symptoms of schizophrenia. This review summarizes the state of knowledge of adult neurogenesis in schizophrenia and raises important unanswered questions. We highlight how alterations in signalling molecules in the local and peripheral environments in schizophrenia may regulate adult neurogenesis in the human subgranular zone of the hippocampus and the subependymal zone (SEZ). Recent findingsCell proliferation and density of mature neurons are reduced in the hippocampus, yet the extent of adult neurogenesis remains unexplored in the SEZ in schizophrenia. The human SEZ is a major source of postnatally migrating cortical and striatal inhibitory interneurons, indicating that aberrant neurogenesis may extend to the SEZ and contribute to inhibitory interneuron deficits in schizophrenia. Trophic factors and inflammatory cytokines regulate the generation of new neurons in rodents, suggesting that altered expression of these signalling molecules in the brain, peripheral vasculature and cerebrospinal fluid in schizophrenia may impact adult neurogenesis in both regions. SummaryKnowledge about adult neurogenesis remains scant in schizophrenia. We propose that a more rigorous examination of adult neurogenesis in relation to regulatory signalling molecules will allow us to identify how abnormalities may contribute to the pathophysiology of schizophrenia.

Systematic Review of the Neural Effect of Electroconvulsive Therapy in Patients with Schizophrenia: Hippocampus and Insula as the Key Regions of Modulation

“…Moreover, with regard to the neurotrophic hypothesis of ECT, there is considerable evidence that neurogenesis functions are altered in schizophrenia [ 131 - 133 ]. Animal models of psychosis have demonstrated decreased adult neurogenesis [ 134 - 136 ].…”

“…126,129,130 Moreover, with regard to the neurotrophic hypothesis of ECT, there is considerable evidence that neurogenesis functions are altered in schizophrenia. [131][132][133] Animal models of psychosis have demonstrated decreased adult neurogenesis. [134][135][136] However, animal models of schizophrenia are mainly induced by administering substances known to induce psychotic illness.…”

Evidence for Decreased Density of Calretinin-Immunopositive Neurons in the Caudate Nucleus in Patients With Schizophrenia

“…Although CR-ip and NPY-ip newborn neurons were reported in the adult human CN by Ernst et al (2014), the exact origin of the newly generated interneurons is still unknown. The possible source(s) may be the subependymal zone of the lateral ventricle (Weissleder et al, 2019), striatal astrocytes (Duan et al, 2015;Nato et al, 2015), perivascular sources from striatal vessels (Stanton et al, 2015) or hitherto undiscovered migratory routes. Whereas hippocampal neurogenesis was found to be decreased in patients with SCH (Reif et al, 2006;Weissleder et al, 2019), a remaining question is whether subependymal zone neurogenesis is altered in patients with the condition.…”

“…The possible source(s) may be the subependymal zone of the lateral ventricle (Weissleder et al, 2019), striatal astrocytes (Duan et al, 2015;Nato et al, 2015), perivascular sources from striatal vessels (Stanton et al, 2015) or hitherto undiscovered migratory routes. Whereas hippocampal neurogenesis was found to be decreased in patients with SCH (Reif et al, 2006;Weissleder et al, 2019), a remaining question is whether subependymal zone neurogenesis is altered in patients with the condition. The subependymal zone of the lateral ventricle was examined in SCH, major depression and bipolar disorder and was not found to be histologically different from controls, however specific markers of neurogenesis were not used in that work (Comte et al, 2012).…”

Semaphorins in Adult Nervous System Plasticity and Disease

“…Abnormalities of brain development are increasingly recognized as culprits in the insurgence of schizophrenia. In post-mortem studies of patients with schizophrenia, several brain abnormalities are found, including alterations in cortical thickness, reduced hippocampal volume and hippocampal neurogenesis, neuronal misalignment in cortex and hippocampus, and decreased density of dendritic spines in the prefrontal cortex ( Garey et al, 1998 ; Glantz and Lewis, 2000 ; Wong and Van Tol, 2003 ; van Swam et al, 2012 ; Weissleder et al, 2019 ). These observations suggest that schizophrenia may arise from defects in neuronal migration and synaptic connectivity ( Conrad and Scheibel, 1987 ; Weinberger, 1987 ; Murray, 1994 ; Waddington et al, 1998 ), including excessive synaptic pruning, particularly during adolescence, when usually the first symptoms appear ( Feinberg, 1982 ; Keshavan et al, 1994 ).…”