Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function

Duncan, Gary E.; Moy, Sheryl S.; Pérez, Antonio; Eddy, Dawn M; Zinzow, Wendy; Lieberman, Jeffrey A.; Snouwaert, John N.; Koller, Beverly H.

doi:10.1016/j.bbr.2004.01.008

Cited by 183 publications

(190 citation statements)

References 42 publications

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“…This mutant line is characterized by an aberrant behavioral phenotype, including marked deficiencies in social behavior [21,46] and a tendency for self-injurious responses (present studies), suggesting that the NR1 neo/neo mice might demonstrate repetitive behavior and restricted interests in the nose poke assay. In addition to the autism-like behavioral profile, the deficiency in glutamate function found in the NR1 neo/neo mice may be relevant to the syndrome in humans.…”

Section: Introductionmentioning

confidence: 64%

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Development of a mouse test for repetitive, restricted behaviors: Relevance to autism

Moy

Nadler

Poe

et al. 2008

Behavioural Brain Research

178

182

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Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T + tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1 neo/neo mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T+tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T + tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1 neo/neo mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1 neo/neo mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA-receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Section: Introductionmentioning

confidence: 64%

“…(NR1 neo/neo ) mice were generated from heterozygous breeder pairs, as previously described [21,46]. Briefly, subjects were F1 hybrid mice, generated by the intercross of 129/Ola-NR1 neo/+ female mice with C57BL/6-NR1 neo/+ males.…”

Section: Nr1-nmda Receptor Subunit (Nr1) Hypomorphic Mice-nr1 +/+ Andmentioning

confidence: 99%

Development of a mouse test for repetitive, restricted behaviors: Relevance to autism

Moy

Nadler

Poe

et al. 2008

Behavioural Brain Research

178

182

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“…The NR1 hypomorphic mice (NR1 −/−) exhibit altered phenotypes that include increased locomotor activity (Mohn et al 1999), reduced metabolic activity in the medial prefrontal cortex, anterior cingulate cortex, and the hippocampus (Duncan et al 2002), deficits in social interactions Mohn et al 1999), and deficits in prepulse inhibition of acoustic startle (PPI) Duncan et al 2004;Fradley et al 2005). In addition, the NR1 −/− mice show enhanced sensitivity to amphetamine-induced PPI disruption , but not to the locomotor stimulatory or Fos-inducing effects of amphetamine (Miyamoto et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Duncan

Moy

Lieberman

et al. 2006

Pharmacology Biochemistry and Behavior

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Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1 −/−) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (.05, 0.1, and 0.2 mg/kg). The NR1 −/− mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1 +/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1 −/− mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1 −/− mice, but did reduce startle amplitude in the NR1 +/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1 +/+ and NR1 −/− mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1 +/+ and NR1 −/− mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D 2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.

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“…Myszy mutanty miały obniżoną ekspresją podjednostki NR 1 (NR1neo -/-) o 90-95% normalnego stanu podjednostki NR 1 myszy niezmutowanych. Myszy rzadko wykazywały agresję, ponieważ miały silnie zredukowane zachowanie socjalne (11).…”

Section: Receptory Glutaminianergiczneunclassified

“…Myszy mutanty wykazywały również szereg innych zachowań nienormalnych, takich jak hiperaktywność motoryczną, braki czuciowo-ruchowego bramkowania i obniżoną motywację do znajdowania ukrytego pokarmu (11). Taki rodzaj zmian plejotropowych (polifenicznych) przyczynić się może do obniżenia agresji u zmutowanych myszy.…”

Section: Receptory Glutaminianergiczneunclassified

Role of L-glutamate in aggression

Kania¹,

Wrońska²

2016

Medycyna Weterynaryjna

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Summary L-glutamate is one of major excitatory transmitters (along with aspartic, kainate acids and glycine) in the central nervous system and/or the peripheral nervous system. It mediates interaction through the stimulation of various ionotropic receptors families (ligand gated cation channels) and metabotropic receptor families (G-protein coupled). In this review, we describe the molecular composition of these glutamatergic receptors and discuss their neuropharmacology, particularly with respect to their roles in animal social behaviors and, particularly, in aggression. It is also known, that during aggression different interactions occur in the nervous system among glutamate, serotonin, vasopressin, oxytocin, dopamine, GABA and steroid receptors.

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Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function

Cited by 183 publications

References 42 publications

Development of a mouse test for repetitive, restricted behaviors: Relevance to autism

Development of a mouse test for repetitive, restricted behaviors: Relevance to autism

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Role of L-glutamate in aggression

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