Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?

Good, Peter

doi:10.1016/j.mehy.2012.08.035

Cited by 8 publications

(9 citation statements)

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“…Therefore, the mechanism(s) that may be leading to improvements in symptoms remains unknown. Others have hypothesized that fever may have an impact on the hypothalamic [Sullivan, ; Fischbach, ], locus coeruleus‐noradrenergic [Good, ; Megremi, ; Mehler & Purpura, ], tyrosine systems [Sullivan, ], or related glutamine or taurine release [Good, ]. Additional research is needed to better understand the neural systems that may underlie parent‐observed behavioral changes.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of fever is related to neurological functioning and behavioral change, such as lethargy and irritability, thereby increasing the importance of fever‐reducing treatments [Blatteis, ; Harden, Kent, Pittman, & Roth, ; Mehler & Purpura, ]. Several articles have proposed a unique and potentially important relationship between fever and Autism Spectrum Disorder [ASD; Curran et al, ; Good, ; Herbert, ; Megremi, ; Mehler & Purpura, ; Sullivan, ].…”

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confidence: 99%

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Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection

et al. 2017

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Literature indicates that some children with ASD may show behavioral improvements during fever; however, little is known about the behavioral profiles of these children. This study aims to (a) investigate the subset of children who show parent-reported behavioral improvements associated with fever and (b) compare the demographic, behavioral, and genetic characteristics of this subset of children to children whose parents report no change during fever. Parents of 2,152 children from the Simons Simplex Collection provided information about whether and in which areas their child improved during fever. Children were randomly assigned into discovery or replication samples. In discovery analyses, children who reportedly improved with fever (Improve Group) were compared to those who reportedly did not improve (No Improve Group) on demographics, medical history, ASD symptoms, adaptive skills, and presence of de novo ASD-associated mutations. Significant and marginal results from discovery analyses were tested in the replication sample. Parent reports of 17% of children indicated improvements during fever across a range of domains. Discovery and replication analyses revealed that the Improve Group had significantly lower non-verbal cognitive skills (NVIQ) and language levels and more repetitive behaviors. Groups did not differ on demographic variables, parentreport of current ASD symptoms or the presence of de novo mutations. Understanding the profiles of children who improve during episodes of fever may provide insights into innovative treatments for ASD. Autism Res 2018, 11: 175-184. V C 2017 International Society for Autism Research, Wiley Periodicals, Inc.Lay Summary: This study explored characteristics of children with ASD who are reported to improve during fever.Parents of 17% of children with ASD report improvements across a range of domains during fever including cognition, communication, repetitive behaviors, social interaction, and behavior. Children who are reported to improve during fever have significantly lower non-verbal cognitive skills and language levels and more repetitive behaviors. Understanding the profiles of children who improve during episodes of fever may provide insights into new treatments for ASD.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection

et al. 2017

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“…Some autistic children exhibit improvements in their characteristic autistic behaviors during febrile incidents and the regression of fever may be associated with the onset of ASD (Curran et al, 2007 ; Megremi, 2013 ; Naviaux et al, 2015 ). Several possible explanation for this ameliorative effect have been proposed: (1) the release of glutamine from skeletal muscles (Good, 2013 ); (2) improved brain blood flow (Good, 2011 ); and (3) febrigenesis and the behavioral state changes associated with fever in autism depend on the selective normalization of key components in a functionally impaired locus coeruleus-noradrenergic system (Mehler and Purpura, 2009 ), as shown in Figure 7D . However, the OT concentrations have never been considered as the underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…However, Norton ( 2014 ) reported that a single dose of suramin, a century-old drug for African sleeping sickness, eliminated autism symptoms in adult mice with an experimental form of the disorder (Naviaux et al, 2015 ), and in 2007 it was reported that 83% of children with autism spectrum disorders (ASDs) showed temporary improvement during high fever (Curran et al, 2007 ), prompting us to complete our experiments. Here, we discuss our findings regarding hyperthermia-induced OT release in the context of clinical case reports of behavioral improvement in children with ASDs associated with fever (Curran et al, 2007 ; Good, 2011 , 2013 ; Megremi, 2013 ; Naviaux et al, 2015 ).…”

Section: Introductionmentioning

confidence: 91%

Cyclic ADP-Ribose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus during Social or Psychological Stress in Mice

et al. 2016

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Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulation. Previously, we showed that the intracellular free calcium concentration ([Ca2+]i) that seems to trigger OT release can be elevated by β-NAD+, cADPR, and ADP in mouse oxytocinergic neurons. As these β-NAD+ metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca2+]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35°C to 38.5°C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR-dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38- or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6°C to 37.8°C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8°C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress.

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“…The cause for this phenomenon is unknown, but may be that glutamine synthetase is inhibited by a putative toxin (e.g., propionyl-CoA), which accumulates in PA, or a low concentration of ATP, which is expected in PA, may affect this ATP-dependent enzyme." [13] Plasma glutamine is also low in children with ASD and brain glutamine/ glutamate (glx) also usually low measured by magnetic resonance s pectroscopy (MRS) [14][15][16][17][18] despite their frequent high plasma ammonia [19]. Ghanizadeh: "The low level of plasma glutamine .…”

Section: Letter To Editormentioning

confidence: 99%

Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?

Cited by 8 publications

References 135 publications

Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection

Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection

Cyclic ADP-Ribose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus during Social or Psychological Stress in Mice

Why Do Children With Propionic Acidemia Or Urea Cycle Disorders Rarely Show Autistic Behavior?

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