Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1.
Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo. These results explain why Rac1 and its activator (Kal-7) serve as important mediators of spine enlargement and why constitutive Rac1 activation decreases spine size. This mechanism likely underlies disturbances in glutamatergic neurotransmission that have been frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a signalosome involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.
Hayashi-Takagi
Akiko
A
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Takaki
Manabu
M
Graziane
Nick
N
Seshadri
Saurav
S
Murdoch
Hannah
H
Dunlop
Allan J
AJ
Makino
Yuichi
Y
Seshadri
Anupamaa J
AJ
Ishizuka
Koko
K
Srivastava
Deepak P
DP
Xie
Zhong
Z
Baraban
Jay M
JM
Houslay
Miles D
MD
Tomoda
Toshifumi
T
Brandon
Nicholas J
NJ
Kamiya
Atsushi
A
Yan
Zhen
Z
Penzes
Peter
P
Sawa
Akira
A
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D049229:Dendritic Spines / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D013997:Time Factors; D046509:Tissue Culture Techniques; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D018698:Glutamic Acid; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D020830:rac1 GTP-Binding Protein; C498795:Disc1 protein, rat; C102365:Kalrn protein, rat; C499134:Rac1 protein, rat