Reduced effect of stimulation of AMPA receptors on cerebral O2 consumption in a rat model of autism

Weiss, Harvey R.; Liu, Xia; Grewal, Parneet; Z., Oak

doi:10.1016/j.neuropharm.2012.06.014

Cited by 3 publications

(6 citation statements)

References 40 publications

(58 reference statements)

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“…Thus, the increased consumption was associated with an increase in both flow and O 2 extraction. This is similar to our previous reports using this Eker rat model (Weiss et al 2007, 2012). The increased basal cerebral O 2 consumption in the Eker rats may have important implications for neurological issues found in tuberous sclerosis–ASD.…”

Section: Discussionsupporting

confidence: 93%

“…The increased basal cerebral O 2 consumption in the Eker rats may have important implications for neurological issues found in tuberous sclerosis–ASD. This increased cerebral metabolism does not appear to be related to increased activity in excitatory glutamate receptors (Weiss et al 2007, 2009, 2012). However, some of the increased cerebral oxygen consumption may be related to reduced activity of gamma-aminobutyric acid (GABA) inhibitory receptors (Weiss et al 2008).…”

Section: Discussionmentioning

confidence: 80%

“…It has a defect in Tsc2 that is associated with a significantly elevated cerebral O 2 consumption (Weiss et al 2007, 2012). The major finding of the current study was that inhibition of the TSC-mTOR pathway with rapamycin restored regional cerebral O 2 consumption to normal in the Eker rat, while rapamycin had no significant effect on cerebral metabolism in control animals.…”

Section: Discussionmentioning

confidence: 99%

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Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism–Tuberous Sclerosis

Liu

et al. 2015

Neuromol Med

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Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated. Young (4 weeks) male control Long–Evans and Eker rats were divided into control and rapamycin-treated (20 mg/kg once daily for 2 days) animals. Cerebral regional blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane-anesthetized rats. We found significantly increased basal O2 consumption in the cortex (8.7 ± 1.5 ml O2/min/100 g Eker vs. 2.7 ± 0.2 control), hippocampus, pons and cerebellum. Regional cerebral blood flow and cerebral O2 extractions were also elevated in all brain regions. Rapamycin had no significant effect on O2 consumption in any brain region of the control rats, but significantly reduced consumption in the cortex (4.1 ± 0.3) and all other examined regions of the Eker rats. Phosphorylation of mTOR and S6K1 was similar in the two groups and equally reduced by rapamycin. Thus, a rapamycin-sensitive, mTOR-dependent but S6K1-independent, signal led to enhanced oxidative metabolism in the Eker brain. We found decreased Akt phosphorylation in Eker but not Long–Evans rat brains, suggesting that this may be related to the increased cerebral O2 consumption in the Eker rat. Our findings suggest that rapamycin targeting of Akt to restore normal cerebral metabolism could have therapeutic potential in tuberous sclerosis and autism.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism–Tuberous Sclerosis

Liu

et al. 2015

Neuromol Med

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“…In the basal condition of our current study, we observed significant elevations in cortical and hippocampal blood flow in Eker rats compared to young Long Evans controls. These findings align with previous studies that have reported increased cerebral blood flow (CBF), elevated cerebral oxygen consumption, and enhanced oxygen extraction in this Eker rat model (Weiss et al, 2007 , 2012 ). Previously, we reported no significant effects resulting from the stimulation or blockade of AMPA receptors (Weiss et al, 2009 , 2012 ), GABA A receptor blockade (Weiss et al, 2008 ), or NMDA receptor blockade (Weiss et al, 2007 ) on the elevated regional cerebral blood flow (rCBF) in Eker rats.…”

Section: Discussionsupporting

confidence: 92%

“…We have previously demonstrated that young Eker rats exhibit significantly increased basal cerebral oxygen consumption and blood flow (Weiss et al, 2007 ). Our preliminary investigations also indicated that the heightened cerebral metabolism and blood flow in the young Eker rats were not affected significantly by N -methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blockade or stimulation (Weiss et al, 2007 , 2009 , 2012 ). In contrast rapamycin significantly reduced the basal elevated cerebral blood flow and metabolism in the Eker rat to the level of the control rats (Chi et al, 2015 ).…”

Section: Introductionmentioning

confidence: 81%

Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis

Chi,

Liu,

Fortus

et al. 2024

Neuromol Med

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The manifestations of tuberous sclerosis complex (TSC) in humans include epilepsy, autism spectrum disorders (ASD) and intellectual disability. Previous studies suggested the linkage of TSC to altered cerebral blood flow and metabolic dysfunction. We previously reported a significant elevation in cerebral blood flow in an animal model of TSC and autism of young Eker rats. Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin could restore normal oxygen consumption and cerebral blood flow. In this study, we investigated whether inhibiting a component of the mTOR signaling pathway, p70 ribosomal S6 kinase (S6K1), would yield comparable effects. Control Long Evans and Eker rats were divided into vehicle and PF-4708671 (S6K1 inhibitor, 75 mg/kg for 1 h) treated groups. Cerebral regional blood flow (14C-iodoantipyrine) was determined in isoflurane anesthetized rats. We found significantly increased basal cortical (+ 32%) and hippocampal (+ 15%) blood flow in the Eker rats. PF-4708671 significantly lowered regional blood flow in the cortex and hippocampus of the Eker rats. PF-4708671 did not significantly lower blood flow in these regions in the control Long Evans rats. Phosphorylation of S6-Ser240/244 and Akt-Ser473 was moderately decreased in Eker rats but only the latter reached statistical significance upon PF-4708671 treatment. Our findings suggest that moderate inhibition of S6K1 with PF-4708671 helps to restore normal cortical blood flow in Eker rats and that this information might have therapeutic potential in tuberous sclerosis complex and autism.

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The BOLD signal and neurovascular coupling in autism

Reynell¹,

Harris²

2013

Developmental Cognitive Neuroscience

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Reduced effect of stimulation of AMPA receptors on cerebral O2 consumption in a rat model of autism

Cited by 3 publications

References 40 publications

Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism–Tuberous Sclerosis

Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism–Tuberous Sclerosis

Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis

The BOLD signal and neurovascular coupling in autism

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