I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all...  Read more

I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all together, it may be useful to have a working hypothesis that a candidate susceptibility gene product for schizophrenia, DISC1, may have an additional role in regulating synaptic functions via Rho-family GTPases, probably in some association with LIS1.

This paper may attract researchers on schizophrenia in another context. The authors used D-serine as a trigger of calcium signaling via activation of the NMDA receptor. Although several genes coding for proteins that are involved in synthesis and degradation of D-serine have been associated with schizophrenia, pathophysiological roles for D-serine remain to be elucidated. In this sense, the impact of D-serine in activation of Cdc42 and synaptic morphology may have implications for schizophrenia research. Personally speaking, it is the most interesting point in this paper that the authors use D-serine in this type of experiment.

This is another important study supporting the glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia we proposed in 2002 (Moises et al., 2002). The glial synaptic destabilization hypothesis is based on the landmark 1997 paper by Pfrieger and Barres and the tripartite synapse model suggested by Philip Haydon and coworkers (Araque et al., 1999; Pascual et al., 2005). In reference to its underlying principle, the glial growth factors deficiency and synaptic destabilization hypothesis might also more conveniently and briefly be designated as the weakened tripartite-synapse hypothesis of schizophrenia.

References:
Moises HW, Zoega T, Gottesman II. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry. 2002;2:8. Abstract

Moises HW, Gottesman II. Does glial asthenia predispose to schizophrenia? Arch Gen Psychiatry 2004; 61:1170. Abstract

Pfrieger FW, Barres BA. Synaptic efficacy enhanced by glial cells in vitro. Science. 1997;277:1684-7. Abstract

Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999; 22:208-15. Abstract

Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG. Astrocytic purinergic signaling coordinates synaptic networks. Science 2005; 310: 113-6. Abstract

View all comments by Hans W. Moises

Peirce's paper is an exciting addition to the white matter hypothesis in schizophrenia. (Note: many of the authors of this paper are colleagues of ours at the Conte Center investigating white matter in schizophrenia at Mount Sinai.) As noted in the news story, findings from a number of different areas are beginning to come together in support of the white matter hypothesis in schizophrenia. Genetic findings in myelin-related genes, as outlined and referenced above, are demonstrating increased susceptibility to schizophrenia. Imaging findings from diffusion tensor studies are demonstrating abnormalities across multiple brain areas (reviewed in Kubicki et al., 2005), with more recent studies showing that specific white matter tracts are not only abnormal in schizophrenia, but are associated with symptomatology and cognitive deficits (Kubicki et al., 2002;   Read more

Peirce's paper is an exciting addition to the white matter hypothesis in schizophrenia. (Note: many of the authors of this paper are colleagues of ours at the Conte Center investigating white matter in schizophrenia at Mount Sinai.) As noted in the news story, findings from a number of different areas are beginning to come together in support of the white matter hypothesis in schizophrenia. Genetic findings in myelin-related genes, as outlined and referenced above, are demonstrating increased susceptibility to schizophrenia. Imaging findings from diffusion tensor studies are demonstrating abnormalities across multiple brain areas (reviewed in Kubicki et al., 2005), with more recent studies showing that specific white matter tracts are not only abnormal in schizophrenia, but are associated with symptomatology and cognitive deficits (Kubicki et al., 2002; Kubicki et al., 2003; Nestor et al., 2004). Postmortem examination is revealing that oligodendrocytes are decreased in number and abnormally spaced in patients with schizophrenia (Hof et al., 2002; Hof et al., 2003). These converging data argue strongly for the involvement of myelin, oligodendrocytes, and white matter in schizophrenia.

We continue to examine various aspects of white matter involvement in schizophrenia with the hope of providing both translational data (i.e., the relationship between symptom severity or independent living and white matter coherence) and further basic science data that may shed some light on upstream events that contribute to myelin and oligodendrocyte deficits. These new data by the Owen and O'Donovan group are a valuable contribution.

References:
Hof PR, Haroutunian V, Copland C, Davis KL, Buxbaum JD. Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem Res. 2002 Oct;27(10):1193-200. Abstract

Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry. 2003 Jun 15;53(12):1075-85. Abstract

Kubicki M, McCarley R, Westin CF, Park HJ, Maier S, Kikinis R, Jolesz FA, Shenton ME. A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res. 2005 Jul 13; [Epub ahead of print] Abstract

Kubicki M, Westin CF, Maier SE, Frumin M, Nestor PG, Salisbury DF, Kikinis R, Jolesz FA, McCarley RW, Shenton ME. Uncinate fasciculus findings in schizophrenia: a magnetic resonance diffusion tensor imaging study. Am J Psychiatry. 2002 May;159(5):813-20. Abstract

Kubicki M, Westin CF, Nestor PG, Wible CG, Frumin M, Maier SE, Kikinis R, Jolesz FA, McCarley RW, Shenton ME. Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study. Biol Psychiatry. 2003 Dec 1;54(11):1171-80. Erratum in: Biol Psychiatry. 2004 Mar 15;55(6):661. Abstract

Nestor PG, Kubicki M, Gurrera RJ, Niznikiewicz M, Frumin M, McCarley RW, Shenton ME. Neuropsychological correlates of diffusion tensor imaging in schizophrenia. Neuropsychology. 2004 Oct;18(4):629-37. Abstract

The Peirce et al. paper represents an important contribution to understanding the possible mechanisms through which genetic risk factors could contribute to the pathophysiology of schizophrenia. Studies of SNPs in candidate genes for schizophrenia are most clearly related to mechanism when the SNP changes amino acid sequence (rarely), or when the SNP changes mRNA expression (commonly postulated, but less often demonstrated). Studies combining SNP and mRNA analyses are challenging, and Peirce et al. provide a novel approach—by measuring the relative amount of mRNA expressed from the variant and the wild-type alleles in brain tissue from heterozygotes. They demonstrated relatively reduced expression from the variant allele. It must be noted however, that these studies were carried out in brain tissue from individuals described as being “free from psychiatric or neurological disorder at time of death” (not schizophrenia samples as suggested by the SRF news story [Editor's note: since corrected]), and the total expression of CNP mRNA was not determined. While CNP mRNA...  Read more

The Peirce et al. paper represents an important contribution to understanding the possible mechanisms through which genetic risk factors could contribute to the pathophysiology of schizophrenia. Studies of SNPs in candidate genes for schizophrenia are most clearly related to mechanism when the SNP changes amino acid sequence (rarely), or when the SNP changes mRNA expression (commonly postulated, but less often demonstrated). Studies combining SNP and mRNA analyses are challenging, and Peirce et al. provide a novel approach—by measuring the relative amount of mRNA expressed from the variant and the wild-type alleles in brain tissue from heterozygotes. They demonstrated relatively reduced expression from the variant allele. It must be noted however, that these studies were carried out in brain tissue from individuals described as being “free from psychiatric or neurological disorder at time of death” (not schizophrenia samples as suggested by the SRF news story [Editor's note: since corrected]), and the total expression of CNP mRNA was not determined. While CNP mRNA expression is reported to be lower in schizophrenia, and Peirce et al. demonstrate the variant allele is a risk factor for schizophrenia in studies of genetic association, it remains uncertain to what extent the lower CNP mRNA expression in schizophrenia is related to genetic variation or to other factors. CNP mRNA differences in expression between schizophrenia and control samples appear to be of different magnitude in different brain regions from the same cases (Katsel et al., 2005). This could represent non-genetic effects. However, genetic variation in CNP could also be more or less likely to be expressed in different brain regions. In this regard, the samples used in the Peirce et al. study were mixed, coming from frontal, parietal, or temporal cortex. Studies with larger sample sizes, and of schizophrenia as well as control tissues, will be needed to test these possibilities.