Faulkner RL, Jang MH, Liu XB, Duan X, Sailor KA, Kim JY, Ge S, Jones EG, Ming GL, Song H, Cheng HJ.
Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci U S A.
2008 Sep 16
Comments on News and Primary Papers
Comment by: Jill Morris
, Kate Meyer
Submitted 3 October 2008
Posted 6 October 2008
I recommend the Primary Papers
The elegant research by Faulkner and colleagues, along with their previous work (Duan et al., 2007), clearly demonstrates a role for DISC1 in regulating the timing of neuronal development in the adult brain. The loss of Disc1 in adult-born dentate granule cells resulted in aberrant axonal targeting and accelerated mossy fiber maturation. Although it is hypothesized that the hippocampus is involved in the pathophysiology of schizophrenia, the cellular and molecular underpinnings of hippocampal dysfunction are unknown. However, it is becoming apparent that Disc1 is a regulator of granule cell integration and maturation in the adult hippocampus. The function of adult-born granule cells and the contribution they make to hippocampal function is, of course, yet to be fully elucidated. In the context of schizophrenia, though, it may be that abnormal incorporation of newborn granule cells into the hippocampal network—perhaps caused by mutations in key genes such as Disc1—is a post-developmental trigger which leads to the onset of disease symptoms.
The finding that Disc1 regulates mossy fiber targeting and synapse formation is also intriguing on a more general level. There is much research suggesting that schizophrenia is a disease of the synapse, likely involving several neurotransmitter systems. A role for Disc1 in axon outgrowth and synapse formation would certainly be a means through which Disc1 disruption could affect the hippocampal trisynaptic circuit. Next, we as researchers will have to determine the molecular mechanisms by which Disc1 is regulating neuronal development and axonal targeting. Based on the work in the developing and adult brain, Disc1 has multiple cellular roles involving a long list of interactors. The challenge is determining which Disc1 functions and pathways are relevant to the schizophrenia phenotype.
Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, 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. Abstract
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