Dataset Information

Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction.

ABSTRACT: Several studies have found decreased levels of ?-3 polyunsaturated fatty acids in the brain and blood of schizophrenia patients. Furthermore, dietary ?-3 supplements may improve schizophrenia symptoms and delay the onset of first-episode psychosis. We used an animal model of NMDA receptor hypofunction, NR1KD mice, to understand whether changes in glutamate neurotransmission could lead to changes in brain and serum fatty acids. We further asked whether dietary manipulations of ?-3, either depletion or supplementation, would affect schizophrenia-relevant behaviors of NR1KD mice. We discovered that NR1KD mice have elevated brain levels of ?-6 fatty acids regardless of their diet. While ?-3 supplementation did not improve any of the NR1KD behavioral abnormalities, ?-3 depletion exacerbated their deficits in executive function. Omega-3 depletion also caused extreme mortality among male mutant mice, with 75% mortality rate by 12 weeks of age. Our studies show that alterations in NMDAR function alter serum and brain lipid composition and make the brain more vulnerable to dietary ?-3 deprivation.

SUBMITTER: Islam R

PROVIDER: S-EPMC5441542 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction.

Islam Rehnuma R Trépanier Marc-Olivier MO Milenkovic Marija M Horsfall Wendy W Salahpour Ali A Bazinet Richard P RP Ramsey Amy J AJ

NPJ schizophrenia 20170322

Several studies have found decreased levels of ω-3 polyunsaturated fatty acids in the brain and blood of schizophrenia patients. Furthermore, dietary ω-3 supplements may improve schizophrenia symptoms and delay the onset of first-episode psychosis. We used an animal model of NMDA receptor hypofunction, NR1KD mice, to understand whether changes in glutamate neurotransmission could lead to changes in brain and serum fatty acids. We further asked whether dietary manipulations of ω-3, either depleti ...[more]

PMID: 28560258

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Project description:Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N-methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the ?-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency ?-oscillations (LF?) and high-frequency ?-oscillations (HF?) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HF? and LF? in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LF? (? 34 Hz at 32°C) in layer V and HF? (? 54 Hz) in layer III of the same cortical column. In controls, HF? and LF? were independent, and pyramidal neurons recorded in layer III were entrained by HF?, but not by LF?. Sub-anesthetic concentrations of ketamine selectively decelerated HF? by 22 Hz (EC(50)=2.7 ?M), to match the frequency of LF? in layer V. This caused phase coupling of the two ?-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LF? in layer V. PCP similarly decelerated HF? by 22 Hz (EC(50)=0.16 ?M), causing cross-layer phase coupling of ?-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HF?, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HF?. The NMDA receptor hypofunction-induced phase coupling of the normally independent ?-generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HF? and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HF? could be the target for improved antipsychotic therapy.

Dataset Information

Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction.

Publications

Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction.

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