Abstract
Disturbance in the synapse has been suggested in the pathology of schizophrenia, especially through examination of autopsied brains from patients with the disease. Nonetheless, it has been unclear whether and how such disturbance is associated with the onset and progression of the disease in young adulthood. Some studies with magnetic resonance spectroscopy (MRS) have suggested that overpruning of dendritic spines may occur in the prodromal and early stages of schizophrenia. In addition, our recent study indicates that DISC1, a promising risk factor for schizophrenia, has a crucial role in the maintenance of the dendritic spine in association with activation of the NMDA-type glutamate receptor. 1 Disturbance of spine maintenance can be linked to aberrant synaptic pruning during postnatal brain maturation. Biological studies with genetic models may provide us with an opportunity to validate experimentally the synaptic pruning theory for schizophrenia. An integrative strategy of brain imaging and cell biology may be a promising approach to address a key biological question for mental illnesses.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 211-212 |
| Number of pages | 2 |
| Journal | Communicative and Integrative Biology |
| Volume | 4 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 2011 |
Keywords
- DISC1
- Dendritic spine
- Magnetic resonance spectroscopy (MRS)
- Schizophrenia
- Synaptic pruning
ASJC Scopus subject areas
- General Agricultural and Biological Sciences
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In: Communicative and Integrative Biology, Vol. 4, No. 2, 03.2011, p. 211-212.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Readdressing synaptic pruning theory for schizophrenia
T2 - Combination of brain imaging and cell biology
AU - Hayashi-Takagi, Akiko
AU - Barker, Peter B.
AU - Sawa, Akira
N1 - Funding Information: %POPUEJTUSJCVUF has a crucial role in the maintenance of (MRS) by using conventional localized the dendritic spine in association with spectroscopy methods.6-8 Although find-activation of the NMDA-type glutamate ings have sometimes been discordant, receptor.1 Disturbance of spine mainte- several reasonably consistent patterns nance can be linked to aberrant synaptic have emerged. For instance, 31P MRS pruning during postnatal brain matu- studies have found decreased phospho-ration. Biological studies with genetic monoesters (PME) and increased phos-models may provide us with an opportu- phodiesters (PDE) in the frontal lobes nity to validate experimentally the syn- of patients with schizophrenia relative to aptic pruning theory for schizophrenia. normal control subjects.9 It appears that An integrative strategy of brain imag- the increased PDE levels are found only ing and cell biology may be a promis- in the early phases of schizophrenia, not ing approach to address a key biological in chronic cases.10,11 This suggests that question for mental illnesses. schizophrenia patients have abnormal phospholipid metabolism in their frontal Schizophrenia is a debilitating and com-lobe membranes, with decreased synthe-mon mental disorder, and its mechanistic sis and increased breakdown of neuronal understanding at the molecular and cellu-membrane phospholipids. This finding is lar levels is awaited. Involvement of genetic likely to be consistent with a proposal that factors in the etiopathogenesis of schizo-the synaptic defects found in autopsied phrenia is clear, but no specific causal brains from patients with schizophrenia gene, such as huntingtin for Huntington’s might come from overpruning of the syn-disease, has been reported for this mental apse,12 that is, excess loss of the neuronal disorder. Instead, a combination of genetic membrane.13 and environmental factors may contribute What possible mechanisms could synergistically to the pathology from early underlie such synaptic changes in association with schizophrenia? Genetic in vivo. Overexpression of DISC1 (gain density on prefrontal cortical pyramidal neurons in 4.Glantz LA, Lewis DA. Decreased dendritic spine susceptibility factors for schizophrenia of function) also augments inhibition of schizophrenia. Arch Gen Psychiatry 2000; 57:65-73. may provide us with important clues. For Kal-7, leading to insufficient activation Noguchi J. Structural dynamics of dendritic spines Kasai H, Fukuda M, Watanabe S, Hayashi-Takagi A, the past several years, efforts to elucidate of Rac1 and spine shrinkage in prolonged in memory and cognition. Trends Neurosci 2010; functions of genetic factors in schizophre-neuron culture. Taken together, various 33:121-9. nia have been made in many laborato-alterations in DISC1, both loss and gain copy: current and future applications in psychiatric Lyoo IK, Renshaw PF. Magnetic resonance spectros- ries, including ours. As described above, of functions, apparently result in a com-research. Biol Psychiatry 2002; 51:195-207. none of the genes cause this disease per mon synaptic disturbance. Longitudinal Duyn JH, Moonen CT, et al. Regionally specific Bertolino A, Nawroz S, Mattay VS, Barnett AS, se; nonetheless many of the susceptibil-study of synaptic morphology and func-pattern of neurochemical pathology in schizophre- ity factors are enriched in the synapse.14 tion with genetic animal models of schizo-nia as assessed by multislice proton magnetic reso- Therefore, we hypothesized that these fac-phrenia, such as DISC1 mutant models, 153:1554-63.nance spectroscopic imaging. Am J Psychiatry 1996; tors may be functionally related with one from early development to adulthood may Steen RG, Hamer RM, Lieberman JA. Measurement another, forming biologically significant provide an opportunity to validate this of brain metabolites by 1H magnetic resonance spec- “pathways” and playing a role in synaptic synaptic pruning theory for schizophrenia reviewandmeta-analysis.Neuropsychopharmacologytroscopy in patients with schizophrenia: a systematic maintenance.2 Thus, genetic variations experimentally. 2005;30:1949-62. or mutations in these factors may lead In summary, we introduce the synap-resonance spectroscopyinschizophrenia:method-Keshavan MS, Stanley JA, Pettegrew JW. Magnetic to overpruning of the synapse in young tic pruning theory for schizophrenia and ological issues and findings—part II. Biol Psychiatry adolescents. Disrupted-in-Schizophrenia summarize efforts to validate this notion 2000;48:369-80. 1 (DISC1) may be a leading candidate experimentally. Combination of brain Rylett RJ, Morrison-Stewart S, et al. Membrane Stanley JA, Williamson PC, Drost DJ, Carr TJ, for understanding synaptic change in imaging, especially MRS, with patients phospholipid metabolism and schizophrenia: an in schizophrenia. with schizophrenia together with longitu-13:209-15.vivo 31P-MR spectroscopy study. Schizophr Res 1994; We have found that the protein bind-dinal studies of genetic animal models for 11. Stanley JA, Williamson PC, Drost DJ, Carr TJ, Rylett ing of DISC1 and Kalirin-7 (Kal-7) is the disease may be an attractive approach RJ, Malla A, et al. An in vivo study of the prefrontal regulated by activation of the NMDA-to address this question. illness viaphosphorusmagnetic resonancespectros-cortex of schizophrenic patients at different stages of type glutamate receptor.1 Kal-7 is known copy. Arch Gen Psychiatry 1995; 52:399-406. to regÜulate structural plasticity of the d-en-BOEAcknFowledTgement#s JPT12. FDeinberg IJ. SFchizopOhrenia: cDaused bFy a fault in pro- dritic spine via controlling Rac1 activity.15 This work was supported by USPHS grants Psychiatr Res 1982; 17:319-34.grammed synaptic elimination during adolescence? J Expression of Kal-7 is reportedly decreased of MH-084018 Silvo O. Conte center 13. Pettegrew JW, Keshavan MS, Minshew NJ. 31P in brains from patients with schizophre-(A.S.), MH-069853 (A.S.), MH-085226 nuclear magnetic resonance spectroscopy: neurode- nia.16DISC1 inhibits Kal-7% from aPccessing O(AP.S.),UMH-08E875J3T(A.S.U),aSswJelClasVUF 19:35-53. Rac1; whereas, once the NMDA receptor grants from Stanley (A.S.), RUSK (A.S.), 14. Harrison PJ, West VA. Six degrees of separation: on is activated, DISC1 dissociates from Kal-7 S-R (A.S.), Maryland Stem Cell Research genes converge on synapses, glutamate and NMDA the prior probability that schizophrenia susceptibility and enables it to activate Rac1. Rac1 activ-Fund (A.S.) and NARSAD (A.H.T. and receptors. Mol Psychiatry 2006; 11:981-3. ity is required for spine growth, but excess A.S.). Penzes P, Jones KA. Dendritic spine dynamics—a key activity is against spine maintenance.17,18 role for kalirin-7. Trends Neurosci 2008; 31:419-27.
PY - 2011/3
Y1 - 2011/3
N2 - Disturbance in the synapse has been suggested in the pathology of schizophrenia, especially through examination of autopsied brains from patients with the disease. Nonetheless, it has been unclear whether and how such disturbance is associated with the onset and progression of the disease in young adulthood. Some studies with magnetic resonance spectroscopy (MRS) have suggested that overpruning of dendritic spines may occur in the prodromal and early stages of schizophrenia. In addition, our recent study indicates that DISC1, a promising risk factor for schizophrenia, has a crucial role in the maintenance of the dendritic spine in association with activation of the NMDA-type glutamate receptor. 1 Disturbance of spine maintenance can be linked to aberrant synaptic pruning during postnatal brain maturation. Biological studies with genetic models may provide us with an opportunity to validate experimentally the synaptic pruning theory for schizophrenia. An integrative strategy of brain imaging and cell biology may be a promising approach to address a key biological question for mental illnesses.
AB - Disturbance in the synapse has been suggested in the pathology of schizophrenia, especially through examination of autopsied brains from patients with the disease. Nonetheless, it has been unclear whether and how such disturbance is associated with the onset and progression of the disease in young adulthood. Some studies with magnetic resonance spectroscopy (MRS) have suggested that overpruning of dendritic spines may occur in the prodromal and early stages of schizophrenia. In addition, our recent study indicates that DISC1, a promising risk factor for schizophrenia, has a crucial role in the maintenance of the dendritic spine in association with activation of the NMDA-type glutamate receptor. 1 Disturbance of spine maintenance can be linked to aberrant synaptic pruning during postnatal brain maturation. Biological studies with genetic models may provide us with an opportunity to validate experimentally the synaptic pruning theory for schizophrenia. An integrative strategy of brain imaging and cell biology may be a promising approach to address a key biological question for mental illnesses.
KW - DISC1
KW - Dendritic spine
KW - Magnetic resonance spectroscopy (MRS)
KW - Schizophrenia
KW - Synaptic pruning
UR - http://www.scopus.com/inward/record.url?scp=80155172483&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80155172483&partnerID=8YFLogxK
U2 - 10.4161/cib.4.2.14492
DO - 10.4161/cib.4.2.14492
M3 - Article
C2 - 21655443
AN - SCOPUS:80155172483
SN - 1942-0889
VL - 4
SP - 211
EP - 212
JO - Communicative and Integrative Biology
JF - Communicative and Integrative Biology
IS - 2
ER -