Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1

Abstract

Schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.

Figure 1. Long-term neurodevelopmental processes, which are disturbed in schizophrenia (SZ)

The upper part depicts normal corticogenesis: radial migration of the neural progenitor cells from the subventricular zone towards the cortical plate to form the well defined cortical layers and elimination of connections in adolescence. The lower part shows details of the processes that might go wrong in SZ. SZ is primarily an adult psychiatric disorder in which disturbances elicited by susceptibility genes and environmental insults (risks/insults) during early development (indicated by three pink stars in the left side) disturb postnatal brain maturation. These factors, including genetic (e.g., Neuregulin-1/ErbB4 and DISC1) and environmental factors (e.g., birth hypoxia and congenital infection), are likely to impair some of the crucial processes in early development, including progenitor cell proliferation, neuronal migration, and dendritic arborization and outgrowth. Independent of such initial risks/insults, disease-associated intrinsic factors may also directly affect postnatal brain maturation (indicated by two pink central stars). The accumulation of such deleterious insults results in overall disturbance of proper postnatal brain maturation, which includes maturation of interneurons and dopaminergic projections, pruning of glutamate synapses, and myelination. Therefore, it is crucial to understand the mechanisms that underlie the long-term progression to the full disease manifestation in young adulthood to enable development of novel etiology-based therapeutic strategies. In this figure, interneuron maturation is plotted by an increased response of interneurons to dopamine D2 agonists in the prefrontal cortex [26], whereas mesocortical dopaminergic projection is based on the levels of tyrosine hydroxylase [34]. The relative amount/level of glutamatergic synapse density and myelination are depicted according to the previous publications [38, 47]. Molecular cascades involving NRG1/ErbB4 and DISC1 in each developmental stage (indicated by rectangles) are described in Figure 2. CP, cortical plate; SVZ, subventricular zone.

Figure 2. Convergence of two pleiotropic pathways: DISC1 and Neuregulin-1 (NRG1)–ErbB4, which are disturbed in schizophrenia

(a) In neuronal progenitor cells, DISC1 plays an important role in regulating the Wnt-pathway by directly binding with GSK3β and modulating the stability of β-catenin. DISC1 is also localized in the nucleus where it potentially encounters intracellular domains of ErbB4 (ErbB4*) and neuregulin-1 (NRG1*). (b) In postmitotic neurons pre/perinatally DISC1 interacts with PCM1 (another risk gene for SZ) and BBS in the dynein motor complex in association with the centrosome and plays a key role in migration and arborization. DISC1 might contribute to outgrowth by interacting with many other cytoskeleton-associated proteins. Substantial levels of nuclear DISC1 are also observed. (c) In postnatal brains, neuronal connectivity among pyramidal neurons, interneurons, and dopaminergic projection from the ventral tegmental area underlies proper functions of the cortex. At the postsynaptic density (PSD) of the pyramidal neurons, in conjunction with the NMDA-type glutamate receptor, NRG1–ErbB4 and DISC1 cascades are likely to converge. These two cascades may also converge in the nucleus, mediating gene transcription. DISC1 also interacts with PDE4, regulating cAMP signaling. α7, alpha7 nicotinic acetylcholine receptor; ATF4, activating transcription factor 4; BBS, Bardet-Biedl syndrome; DBZ, DISC1-binding zinc-finger protein; DA-R, dopamine receptor; FEZ1, fasciculation and elongation protein zeta 1; GABAR, gamma-aminobutyric acid receptor; Grb2, growth factor receptor bound protein 2; GSK3β, glycogen synthase kinase 3β; KIF5, kinesin family member 5; LIS1, lissencephaly-1; NDEL1, nuclear distribution element-like 1; NMDAR, NMDA receptor; PCM1, pericentriolar material 1; PML, promyelocytic leukemia; PSD95, post-synaptic density protein 95.