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Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion.

Ma TM, Abazyan S, Abazyan B, Nomura J, Yang C, Seshadri S, Sawa A, Snyder SH, Pletnikov MV - Mol. Psychiatry (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Solomon H. Snyder Department of Neuroscience, Baltimore, MD, USA.

ABSTRACT
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.

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DISC1 mutant mice exhibit greater responses to an NMDA antagonist, MK-801, and D-serine treatment[a] Locomotor activity in open field of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control male mice, mutant male mice display significantly greater activity in response to MK-801. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[b] Locomotor activity in open field of female mice before and after treatments with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control female mice, mutant female mice exhibit significantly higher locomotor activity in response to MK-801. Compared to control female mice, mutant female mice show significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[c] PPI of the acoustic startle of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). p4–20 are the intensities of pre-pulses above the background noise level (70dB). Compared to control male mice, mutant male mice display greater MK-801 induced impairment in PPI at P4 and P8. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine at P4. Numbers of mice in each group are indicated on the graph.[d] PPI of the acoustic startle of female mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Numbers of mice in each group are indicated on the graph.
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Figure 5: DISC1 mutant mice exhibit greater responses to an NMDA antagonist, MK-801, and D-serine treatment[a] Locomotor activity in open field of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control male mice, mutant male mice display significantly greater activity in response to MK-801. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[b] Locomotor activity in open field of female mice before and after treatments with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control female mice, mutant female mice exhibit significantly higher locomotor activity in response to MK-801. Compared to control female mice, mutant female mice show significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[c] PPI of the acoustic startle of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). p4–20 are the intensities of pre-pulses above the background noise level (70dB). Compared to control male mice, mutant male mice display greater MK-801 induced impairment in PPI at P4 and P8. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine at P4. Numbers of mice in each group are indicated on the graph.[d] PPI of the acoustic startle of female mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Numbers of mice in each group are indicated on the graph.

Mentions: Our biochemical studies established that mutant DISC1 destabilizes and depletes SR, leading to decreased levels of D-serine. As D-serine activates NMDA receptors, we wondered whether mutant mice would display behavioral alterations consistent with diminished NMDA receptor transmission. We treated mice with an NMDA antagonist, MK-801 (0.3 mg/kg, i.p.), which is commonly used to probe behavioral consequences of NMDA receptor dysfunction61. MK-801 elicits substantially greater locomotor stimulation in male and female mutant mice compared to control mice (Figure 5a and b). Repeated measures ANOVA reveals a significant group effect for male mice, F(1,479)=5.9, p<0.05; and female mice, F(1,429)=5.3, p<0.05. We also evaluated the influence of D-serine on MK-801-induced hyperactivity in mice. Our pilot experiments had shown that a high dose of D-serine (i.e., 2.7g/kg, i.p.24, 62–64) is needed to decrease MK-801-induced hyperactivity in mice. D-serine reduces the hyperactivity of mutants much more than wild-type animals (Figure 5a and b). Specifically, in male mice, D-serine does not alter hyperactivity in control mice but diminishes locomotor activity of mutant mice by 70–80%. ANOVA for the treatment data in male mice shows a significant time × group × treatment interaction, F(23,911)=1.6, p=0.041. A lower level ANOVA for the treatment data demonstrates a significant effect of treatment with D-serine in the mutant group, F(1,311)=53.5, p<0.001 but not the control one, F=1.3, p=0.3. In female mice, D-serine treatment reduces locomotor activity in both control and mutant mice but to a greater extent in mutant mice. ANOVA for the treatment data reveals a significant effect of treatment for control female mice, F(1,477)=14.8, p<0.001, and mutant female mice, F(1,527)=60.3, p<0.01. Comparing the data for locomotor activity after D-serine treatment between control and mutant female mice indicates a significant group by time interaction, F(23,575)=1.7, p=0.023. Post-hoc comparisons reveal a significantly greater locomotor activity in control mice vs. mutant mice at 20–23 time intervals (Figure 5a and b).


Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion.

Ma TM, Abazyan S, Abazyan B, Nomura J, Yang C, Seshadri S, Sawa A, Snyder SH, Pletnikov MV - Mol. Psychiatry (2012)

DISC1 mutant mice exhibit greater responses to an NMDA antagonist, MK-801, and D-serine treatment[a] Locomotor activity in open field of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control male mice, mutant male mice display significantly greater activity in response to MK-801. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[b] Locomotor activity in open field of female mice before and after treatments with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control female mice, mutant female mice exhibit significantly higher locomotor activity in response to MK-801. Compared to control female mice, mutant female mice show significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[c] PPI of the acoustic startle of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). p4–20 are the intensities of pre-pulses above the background noise level (70dB). Compared to control male mice, mutant male mice display greater MK-801 induced impairment in PPI at P4 and P8. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine at P4. Numbers of mice in each group are indicated on the graph.[d] PPI of the acoustic startle of female mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Numbers of mice in each group are indicated on the graph.
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Figure 5: DISC1 mutant mice exhibit greater responses to an NMDA antagonist, MK-801, and D-serine treatment[a] Locomotor activity in open field of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control male mice, mutant male mice display significantly greater activity in response to MK-801. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[b] Locomotor activity in open field of female mice before and after treatments with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Compared to control female mice, mutant female mice exhibit significantly higher locomotor activity in response to MK-801. Compared to control female mice, mutant female mice show significantly greater sensitivity to the ameliorative effects of D-serine. Numbers of mice in each group are indicated on the graph.[c] PPI of the acoustic startle of male mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). p4–20 are the intensities of pre-pulses above the background noise level (70dB). Compared to control male mice, mutant male mice display greater MK-801 induced impairment in PPI at P4 and P8. Compared to control male mice, mutant mice also exhibit significantly greater sensitivity to the ameliorative effects of D-serine at P4. Numbers of mice in each group are indicated on the graph.[d] PPI of the acoustic startle of female mice before and after treatment with MK-801 (0.3 mg/kg, i.p.) followed by saline or D-serine injections (2.7 g/kg, i.p.). Numbers of mice in each group are indicated on the graph.
Mentions: Our biochemical studies established that mutant DISC1 destabilizes and depletes SR, leading to decreased levels of D-serine. As D-serine activates NMDA receptors, we wondered whether mutant mice would display behavioral alterations consistent with diminished NMDA receptor transmission. We treated mice with an NMDA antagonist, MK-801 (0.3 mg/kg, i.p.), which is commonly used to probe behavioral consequences of NMDA receptor dysfunction61. MK-801 elicits substantially greater locomotor stimulation in male and female mutant mice compared to control mice (Figure 5a and b). Repeated measures ANOVA reveals a significant group effect for male mice, F(1,479)=5.9, p<0.05; and female mice, F(1,429)=5.3, p<0.05. We also evaluated the influence of D-serine on MK-801-induced hyperactivity in mice. Our pilot experiments had shown that a high dose of D-serine (i.e., 2.7g/kg, i.p.24, 62–64) is needed to decrease MK-801-induced hyperactivity in mice. D-serine reduces the hyperactivity of mutants much more than wild-type animals (Figure 5a and b). Specifically, in male mice, D-serine does not alter hyperactivity in control mice but diminishes locomotor activity of mutant mice by 70–80%. ANOVA for the treatment data in male mice shows a significant time × group × treatment interaction, F(23,911)=1.6, p=0.041. A lower level ANOVA for the treatment data demonstrates a significant effect of treatment with D-serine in the mutant group, F(1,311)=53.5, p<0.001 but not the control one, F=1.3, p=0.3. In female mice, D-serine treatment reduces locomotor activity in both control and mutant mice but to a greater extent in mutant mice. ANOVA for the treatment data reveals a significant effect of treatment for control female mice, F(1,477)=14.8, p<0.001, and mutant female mice, F(1,527)=60.3, p<0.01. Comparing the data for locomotor activity after D-serine treatment between control and mutant female mice indicates a significant group by time interaction, F(23,575)=1.7, p=0.023. Post-hoc comparisons reveal a significantly greater locomotor activity in control mice vs. mutant mice at 20–23 time intervals (Figure 5a and b).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Solomon H. Snyder Department of Neuroscience, Baltimore, MD, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus