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

Abstract

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 depletion or supplementation, would affect schizophrenia-relevant behaviors of NR1KD mice. We discovered that NR1KD mice have elevated brain levels of ω-6 fatty acids regardless of their diet. While ω-3 supplementation did not improve any of the NR1KD behavioral abnormalities, ω-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 ω-3 deprivation.

N-3 (Omega-3) Fatty Acids: Effects on Brain Dopamine Systems and Potential Role in the Etiology and Treatment of Neuropsychiatric Disorders

“…In addition to their effects of dopaminergic function, n-3 PUFAs modulate glutamatergic neurotransmission, which is also aberrant in schizophrenia [198]. Most notably, in mice with reduced levels of NMDA receptors, n-3 PUFAs failed to attenuate any of the behavioral deficits resulting from NMDA receptor hypofunction; however, the NMDA receptor knock-down mice had elevated brain concentrations of n-6 PUFAs regardless of the n-3 PUFA content of their diet, and an n-3 PUFA-deficient diet increased their deficits in executive function [199]. Likewise, in an in vitro study, addition of free, but not membrane-bound, DHA to cultured rat astrocytes or rat brain membrane preparations, decreased glutamate uptake [200].…”

A novel allosteric modulator of the cannabinoid CB1 receptor ameliorates hyperdopaminergia endophenotypes in rodent models

“…GluN1KD (F1 on C57Bl/6J x 129/SvlmJ background) [ 26 ] and DATKO (C57Bl/6J background) [ 24 ] mice were used as murine models of hyperdopaminergia. All mice were tested as follows: Day 1—open-field test and Day 3—pre-pulse inhibition, as previously described [ 28 , 30 , 36 , 37 ].…”

“…GluN1KD (F1 on C57Bl/6J x 129/SvlmJ background) (26) and DATKO (C57Bl/6J background) (24) mice were used as murine models of hyperdopaminergia. All mice were tested as follows: Day 1 -open field test and Day 3 -prepulse inhibition, as previously described (28,30,36,37). CNS exposure, with a brain to plasma ratio of 0.77 from a dose 10 mg/kg, i.p., (AUC 8h brain /AUC 8h plasma ) and brain concentrations of 374 ± 39 ng/mL at 30 min ( Figure S1, Table S1).…”

“…Both the GluN1-Knockdown (GluN1KD) and Dopamine Transporter Knockout (DATKO) mice have increased synaptic dopamine in subcortical regions (23)(24)(25) which is implicated in their phenotypic behavioral changes (24,(26)(27)(28), as well as disrupted sensorimotor gating (29)(30)(31).…”

Remembering Mechanosensitivity of NMDA Receptors

“…Moreover, the list of amphipathic molecules produced and released in physiological settings that could modify NMDAR channel function is potentially very long. In addition to unilateral insertion of such amphipaths into the lipid bilayer NMDAR has been shown to be affected by poly-unsaturated fatty acids (PUFAs) (Calon et al, 2005; Keleshian et al, 2014; Islam et al, 2017), which have also been reported to have significant effect on the transbilayer pressure profile and MS channel activity (Ridone et al, 2018). Consequently, we propose that asymmetric insertion of amphipathic compounds into lipid bilayers made of lipids of different poly-unsaturation can be physiologically relevant for the activity of NMDA receptors.…”