9 September 2007. The schizophrenia susceptibility gene candidate disrupted in schizophrenia 1 (DISC1) may function as a "master regulator" for integrating new neurons into the adult hippocampus, according to a study published online September 6 in Cell. By blocking DISC1 in neural progenitors in adult mice, a team led by investigators at the Johns Hopkins University School of Medicine produced significant alterations in neuronal morphology and positioning, as well as excitation properties.
Hippocampus is one of the major anatomical areas of interest in schizophrenia (see, e.g., Harrison et al., 2004), and these results might help to uncover mechanisms by which the disease negatively impairs memory and other functions subserved by the hippocampus. The study also raises the possibility that some of the hippocampal pathophysiology reported in schizophrenia has origins in later development or adulthood, and may be tractable to adult remediation (Newton and Duman, 2007).
There's always something happening in hippocampus
Until fairly recently, the idea that no new neurons are generated in the adult brain was a basic tenet of neuroscience, a principle that placed great constraints on possible treatments for neurodegenerative diseases and other brain disorders. Since the late 1990s, when the possibility of adult neurogenesis was proposed, this area of research has been unusually contentious. The dust has now settled somewhat, and a general consensus has emerged that while adult neurogenesis in the neocortex is highly unlikely, it is a defining feature of the hippocampus. Indeed, hippocampal neurogenesis now forms the basis for influential theories of depression and the therapeutic actions of antidepressant drugs (Santarelli et al., 2003).
Most studies of hippocampal neurogenesis have focused on cell proliferation and cell fate, and researchers have just begun to turn their attention to the question of how adult-born neurons complete the several migratory and morphological steps necessary for successful integration into existing neural circuits.
Because DISC1 has been shown to promote neurite outgrowth and neuronal migration (Miyoshi et al., 2003; Kamiya et al., 2005; see SRF news story), and because its expression in the adult brain is restricted to the hippocampus, the team led by Hongjun Song and Guo-li Ming of the Johns Hopkins, and Bai Lu of the NIMH explored “the tantalizing possibility that DISC1 may play an important role in regulating the process of adult neurogenesis.” First author Xin Duan of Johns Hopkins and colleagues employed a “single-cell genetic” approach, in which an injected retroviral vector was used to infect mouse neural progenitor cells in the adult hippocampus with a short-hairpin RNA designed to tamp down expression of DISC1.
While DISC1 knockdown did not affect cell fate—over 80 percent of progenitor cells expressing the interfering RNA differentiated into neurons one week after injection, a rate comparable to controls—the researchers observed pronounced effects on cell morphology, migration, and physiology, as well as the overall integration of these new neurons into existing hippocampal circuits.
Duan and colleagues noted that the cell bodies of DISC1 knockdown neurons were much larger than those infected with a control shRNA. Moreover, while developing mouse dentate granule cells typically extend only one apical dendrite that later branches into a dendritic arbor, DISC1 knockdown neurons exhibited multiple primary dendrites, including basal dendrites. These additional dendrites were themselves quite complex; they were much longer and displayed significantly more branching than those seen in normal development.
The morphological alterations had functional consequences. In electrophysiological experiments performed 2 weeks after injection, DISC1 knockdown neurons fired many times more action potentials than controls, suggesting that these neurons had matured much faster than their counterparts.
In normal mice, almost all adult-born neurons remain in the inner two-thirds of the granule cell layer, but neurons in mice treated with shRNA migrated outside this region, some leaving the granule cell layer entirely to settle in the molecular layer.
Figure 1. In this detail from figure 2b of the paper, the green fluorescently labeled neurons were born in the adult hippocampal proliferative zone. The neurons on the left are behaving normally, stopping in the appropriate granule layer of the dentate gyrus. The green neuron on the right, in which DISC1 expression has been knocked down with RNA interference, has overshot the mark, ending up in the molecular layer. [Photo detail courtesy of Cell, from Duan and colleagues, 2007]
DISC1 knockdown neurons were precocious in their synapse formation, with numerous dendritic spines appearing 2 weeks after treatment, a full 2 weeks earlier than in control neurons. Again, these differences profoundly affected function: there was a 20-fold increase in GABAergic spontaneous synaptic currents in DISC1 knockdown cells. "Thus, regulation of DISC1 expression may alter sustained and synchronized firing, a notion with profound implications in cognitive brain function and schizophrenia," the authors write.
Finally, the researchers found evidence that NDEL1, identified in a number of studies as a partner in DISC1's developmental activities (see SRF news story), is also necessary for DISC1's regulation of adult neurogenesis.
Overall, the results paint a picture of greatly accelerated neural development when DISC1 is disrupted. The authors conclude that DISC1 is “a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in development, including adult neurogenesis.”
Reconciling with previous work
The suggestion by Duan and colleagues that DISC1 knockdown releases a regulatory brake to speed up neuronal process elaboration or migration would appear at first glance to contrast with in vitro work (e.g., Miyoshi et al., 2003) and the in vivo study by Sawa and colleagues, which showed impaired dendritic development and retarded migration in developing mouse neocortex when DISC1 expression was suppressed (Kamiya et al., 2005). But given the many differences between the embryonic and adult brain milieus, as well as between the migration patterns in developing neocortex and adult dentate gyrus, it may be the case that DISC1's activity has different end effects at these different settings. Indeed, Duan and colleagues confirmed some of the work of Kamiya and colleagues, reporting preliminary findings that DISC1 appears to spur both dendritic growth in vitro (in hippocampal cells) and migration (in neocortical areas) in early development in their in vivo model.
The findings by Duan and colleagues raise the intriguing possibility that some symptoms of schizophrenia, almost always a late adolescence or adult-onset disease, may be related to disruption of the tightly orchestrated hippocampal neurogenesis seen in the adult brain.—Peter Farley.
Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu X, Yang C-H, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng H-J, Ming G, Lu B, Song H. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Epub 2007 Sep 6. Abstract