Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion.
Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness.
The Solomon H. Snyder Department of Neuroscience, Baltimore, MD, USA.
T M
TM
Ma
S
S
Abazyan
B
B
Abazyan
J
J
Nomura
C
C
Yang
S
S
Seshadri
A
A
Sawa
S H
SH
Snyder
M V
MV
Pletnikov
D000161:Acoustic Stimulation / Q000009:adverse effects; D000661:Amphetamine / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D015259:Dopamine Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007266:Inhibition, Psychological; D007976:Leupeptins; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D019998:Racemases and Epimerases / Q000378:metabolism*; D013216:Reflex, Startle / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D012694:Serine / Q000494:pharmacology; D014162:Transfection; D000099300:Serine Racemase
D000661:Amphetamine; D003513:Cycloheximide; D015853:Cysteine Proteinase Inhibitors; D016291:Dizocilpine Maleate; D015259:Dopamine Agents; D005904:Glial Fibrillary Acidic Protein; D007976:Leupeptins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase; C412476:DISC1 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde