Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

Basu, Alo C.; Tsai, Guochuan E.; Ma, C.; Ehmsen, Jeffrey T.; Mustafa, Asif K.; Han, Liqun; Jiang, Zhong‐Xing; Benneyworth, Michael A.; Froimowitz, Michael P.; Lange, Nicholas; Snyder, Solomon H.; Bergeron, Richard; Coyle, Joseph T.

doi:10.1038/mp.2008.130

Cited by 296 publications

(377 citation statements)

References 37 publications

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“…This role for the NAc to preferentially encode the conditioned response is further supported by the distribution patterns of SR and GlyT1 and the relative effect that the mutants had on conditioned hyperactivity. The reduced expression and extinction of conditioned hyperactivity in the SRÀ/À subjects would then be consistent with the prominent NAc expression of SR, whereas GlyT1 expression is significantly lower in this region (Zafra et al, 1995;Basu et al, 2009). Questions still remain as to the expression of contextspecific sensitization after extinction in the SR and GlyT1 mutants.…”

Section: Discussionmentioning

confidence: 97%

“…Pharmacologic, post-mortem, and genetic findings provide convincing evidence that NMDA receptor hypofunction is a core feature of schizophrenia . The SRÀ/À mouse strain shares behavioral and neuropathological features with schizophrenia (Basu et al, 2009;Devito et al, 2010;. Given the inability of the SRÀ/À mice to extinguish AMPH-induced conditioned hyperactivity, perhaps the NMDA receptor hypofunction in schizophrenia contributes to the high prevalence of substance abuse by impairing their ability to remain abstinent (Coyle, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The SR mutant construct consists of a targeted deletion of exon 1, which encodes the catalytic domain of the enzyme (Basu et al, 2009). Experimental subjects were derived from SR heterozygote (À/ + ) crosses to produce SRnull mutant (À/À) and WT littermate controls.…”

Section: Subjectsmentioning

confidence: 99%

“…The understanding of the functional impact of GlyT1 and SR has been advanced by the use of recombinant mouse lines bearing knockout mutations to the genes encoding these proteins (Tsai et al, 2004;Martina et al, 2005;Basu et al, 2009;Devito et al, 2010;. The SR homozygous knockout (SRÀ/À) mutant and GlyT1 hypomorph (GlyT1À/ + ) represent functionally converse mutations that lead to either NMDA receptor hypofunction (SRÀ/À; Basu et al, 2009) or hyperfunction (GlyT1À/ + ; Martina et al, 2005). Behavioral sensitization and conditioned hyperactivity were tested in these mouse strains to investigate the hypothesis that NMDA receptor signaling plays a critical role in the acquisition and extinction of behavior driven by contextual conditioning.…”

Section: Introductionmentioning

confidence: 99%

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Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

Benneyworth

Coyle

2012

Neuropsychopharmacol

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Repeated intermittent exposure to amphetamine (AMPH) results in the development of persistent behavioral and neurological changes. When drug exposure is paired with a specific environment, contextual cues can control conditioned responses, context-specific sensitization, and alterations in dendritic morphology in the nucleus accumbens (NAc). Intact N-methyl-D-aspartate (NMDA) glutamate receptor signaling is thought to be required for associative learning. The acquisition of context-specific behavioral sensitization to AMPH and extinction of conditioned hyperactivity have been investigated in two genetically modified mouse strains: the serine racemase homozygous knockout (SRÀ/À) and glycine transporter 1 heterozygous mutant (GlyT1À/ + ). These strains have reciprocally altered NMDA receptor co-agonists, D-serine and glycine, levels that result in decreased (SRÀ/À) or increased (GlyT1À/ + ) NMDA receptor signaling. AMPH-induced changes in dendritic morphology in the NAc were also examined. SRÀ/À mice showed reduced expression of context-specific sensitization and conditioned hyperactivity. However, the conditioned hyperactivity in these mice is completely resistant to extinction. Extinction reversed AMPH-induced increased in NAc spine density in wild-type but not SRÀ/À mice. GlyT1 À/ + mice showed a more rapid acquisition of sensitization, but no alteration in the extinction of conditioned hyperactivity. The SRÀ/À data demonstrate that a genetic model of NMDA receptor hypofunction displays a reduced ability to extinguish conditioned responses to drug-associated stimuli. Findings also demonstrate that the morphological changes in the NAc encode conditioned responses that are sensitive to extinction and reduced NMDA receptor activity. NMDA receptor hypofunction may contribute to the comorbidity of substance abuse in schizophrenia.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

Benneyworth

Coyle

2012

Neuropsychopharmacol

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“…D-Serine, an unusual D-amino acid found in mammalian brain, is a physiological ligand of the coagonist site of the NMDARs (3,4); hence, it is pivotal in determining excitability of glutamatergic neurons. D-Serine is endogenously converted from L-serine by serine racemase (SRR) (5) and exists at a high level in the forebrain, where it has a critical role in long-term potentiation (6) and is required for memory formation (6). D-Serine is also involved in NMDAR-mediated neurotoxicity, a process that plays a pathophysiological role in stroke and neurodegenerative diseases (7)(8)(9).…”

mentioning

confidence: 99%

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Sasabe

Miyoshi

Suzuki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

181

145

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/ familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.excitotoxicity | motor neuron disease | neurodegeneration | enzyme histochemistry | 2D-HPLC A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motoneurons in the spinal cord and brain leading to fatal paralysis. Approximately 90% of all cases are sporadic, and the remaining cases are inherited. Of inherited cases, 20% are associated with mutations in superoxide dismutase 1 (SOD1), and 10% involves 43-kDa transactivation response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Despite extensive studies of previously identified ALS-causing genes, the mechanism underlying the selective motoneuronal loss in ALS remains uncertain. Given that the mechanism is at least, in part, common between sporadic and familial ALS, identification of the common pathology is a clue to conquering ALS. Among numerous etiological hypotheses, motoneuronal vulnerability to excitotoxicity is one of the most intensely investigated targets for the treatment of ALS because it is observed in both sporadic and familial ALS with SOD1 mutations (1, 2). For motoneurons, glutamate is the main excitatory transmitter, and excessive motoneuron excitability by glutamate through ionotropic glutamate receptors has been demonstrated.The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a subtype of the ionotropic glutamate receptors and exhibits relatively higher permeability to the calcium ion (Ca ...

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Astrocytic d‐amino acid oxidase degrades d‐serine in the hindbrain

Gonda¹,

Ishii

Mita

et al. 2022

FEBS Letters

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Edited by Ned ManteiD-Serine modulates excitatory neurotransmission by binding to N-methyl-D-aspartate glutamate receptors. D-Amino acid oxidase (DAO) degrades D-amino acids, such as D-serine, in the central nervous system, and is associated with neurological and psychiatric disorders. However, cell types that express brain DAO remain controversial, and whether brain DAO influences systemic D-amino acids in addition to brain D-serine remains unclear. Here, we created astrocyte-specific DAO-conditional knockout mice. Knockout in glial fibrillary acidic protein-positive cells eliminated DAO expression in the hindbrain and increased D-serine levels significantly in the cerebellum. Brain DAO did not influence levels of D-amino acids in the forebrain or periphery. These results show that astrocytic DAO regulates D-serine specifically in the hindbrain.

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Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior

Cited by 296 publications

References 37 publications

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Astrocytic d‐amino acid oxidase degrades d‐serine in the hindbrain

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