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.
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Akiko
A
Hayashi-Takagi
Manabu
M
Takaki
Nick
N
Graziane
Saurav
S
Seshadri
Hannah
H
Murdoch
Allan J
AJ
Dunlop
Yuichi
Y
Makino
Anupamaa J
AJ
Seshadri
Koko
K
Ishizuka
Deepak P
DP
Srivastava
Zhong
Z
Xie
Jay M
JM
Baraban
Miles D
MD
Houslay
Toshifumi
T
Tomoda
Nicholas J
NJ
Brandon
Atsushi
A
Kamiya
Zhen
Z
Yan
Peter
P
Penzes
Akira
A
Sawa
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