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The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders.

Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, MacFabe DF - J Neuroinflammation (2012)

Bottom Line: Propionic acid infusions increased locomotor activity.Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species.These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Kilee Patchell-Evans Autism Research Group, Department of Psychology, University of Western Ontario, London, ON, N6A 5C2, Canada. rthoma2@uwo.ca

ABSTRACT
Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD). Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

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Related in: MedlinePlus

Number of horizontal movements (A), number of vertical movements (B), counterclockwise revolutions (C), clockwise revolutions (D), number of stereotypic movements (E), horizontal movement time (F), and total distance travelled (G), representing abnormal animal behavior following ICV infusions with PPA and PBS. Animals received ICV infusions of PPA ( n = 12) and PBS ( n = 12) twice a day for 7 consecutive days. Behavioral measurements were monitored immediately after each infusion over 30 min. Values represent means ± SE over 7 days. Bars accompanied by asterisks indicate significant difference between treatments at LSD = 0.05, n = 12 per treatment group. PBS, phosphate buffered saline solution; PPA, propionic acid.
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Figure 1: Number of horizontal movements (A), number of vertical movements (B), counterclockwise revolutions (C), clockwise revolutions (D), number of stereotypic movements (E), horizontal movement time (F), and total distance travelled (G), representing abnormal animal behavior following ICV infusions with PPA and PBS. Animals received ICV infusions of PPA ( n = 12) and PBS ( n = 12) twice a day for 7 consecutive days. Behavioral measurements were monitored immediately after each infusion over 30 min. Values represent means ± SE over 7 days. Bars accompanied by asterisks indicate significant difference between treatments at LSD = 0.05, n = 12 per treatment group. PBS, phosphate buffered saline solution; PPA, propionic acid.

Mentions: Locomotor behavior was assessed daily for 7 days, immediately following the second infusion of the day. Prior to behavioral assessment, there was no significant difference in baseline behavior between animals assigned to the PPA and PBS treatment groups. Locomotor activity expressed by horizontal, vertical, and repetitive measures across infusion days, was used to assess animal behavior. Analysis of horizontal activity measures revealed a significant effect of PPA treatment across infusion days for number of horizontal movements, horizontal movement time, and total distance traveled (Figure 1). Propionic acid treated animals traveled further, made more horizontal movements, and spent more time traveling horizontally than PBS treated animals. The number of horizontal movements was significantly higher (F (6, 126) = 3.69, P <0.001) in rats infused with PPA on infusion days 2, 4, 5, 6, and 7 compared to PBS controls (Figure 1a). A similar pattern was observed for horizontal movement time (F (6, 126) = 2.82, P <0.001) (Figure 1f) and total distance traveled (F (6, 126) = 2.08, P <0.001) (Figure 1 g), whereby these behavioral activities were significantly higher in PPA treated animals compared to PBS controls on infusion days 2, 3, 4, 5, 6, and 7. Analysis of the number of vertical movements revealed a significant (F (6, 126) = 2.82, P <0.001) main effect of PPA treatment across infusion days, indicating PPA treated animals made more vertical movements than PBS treated animals on infusion days 3 through 7 (Figure 1b). The results of the repetitive activity measures showed significant increases in counterclockwise revolutions (F (6, 126) = 2.46, P <0.001), clockwise revolutions ( F (6, 126) = 2.40, P <0.001) and number of stereotypic movements ( F (6, 126) = 4.05, P <0.001) in PPA-treated animals across infusion days. On infusion days 3, 4, 5, 6, and 7, animals infused with PPA made more counterclockwise (Figure 1c) and clockwise (Figure 1d) revolutions than PBS controls. Stereotypy showed a similar trend whereby PPA-treated animals displayed more stereotypic movements than PBS animals on infusions days 2 through 7 (Figure 1e).


The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders.

Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, MacFabe DF - J Neuroinflammation (2012)

Number of horizontal movements (A), number of vertical movements (B), counterclockwise revolutions (C), clockwise revolutions (D), number of stereotypic movements (E), horizontal movement time (F), and total distance travelled (G), representing abnormal animal behavior following ICV infusions with PPA and PBS. Animals received ICV infusions of PPA ( n = 12) and PBS ( n = 12) twice a day for 7 consecutive days. Behavioral measurements were monitored immediately after each infusion over 30 min. Values represent means ± SE over 7 days. Bars accompanied by asterisks indicate significant difference between treatments at LSD = 0.05, n = 12 per treatment group. PBS, phosphate buffered saline solution; PPA, propionic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472254&req=5

Figure 1: Number of horizontal movements (A), number of vertical movements (B), counterclockwise revolutions (C), clockwise revolutions (D), number of stereotypic movements (E), horizontal movement time (F), and total distance travelled (G), representing abnormal animal behavior following ICV infusions with PPA and PBS. Animals received ICV infusions of PPA ( n = 12) and PBS ( n = 12) twice a day for 7 consecutive days. Behavioral measurements were monitored immediately after each infusion over 30 min. Values represent means ± SE over 7 days. Bars accompanied by asterisks indicate significant difference between treatments at LSD = 0.05, n = 12 per treatment group. PBS, phosphate buffered saline solution; PPA, propionic acid.
Mentions: Locomotor behavior was assessed daily for 7 days, immediately following the second infusion of the day. Prior to behavioral assessment, there was no significant difference in baseline behavior between animals assigned to the PPA and PBS treatment groups. Locomotor activity expressed by horizontal, vertical, and repetitive measures across infusion days, was used to assess animal behavior. Analysis of horizontal activity measures revealed a significant effect of PPA treatment across infusion days for number of horizontal movements, horizontal movement time, and total distance traveled (Figure 1). Propionic acid treated animals traveled further, made more horizontal movements, and spent more time traveling horizontally than PBS treated animals. The number of horizontal movements was significantly higher (F (6, 126) = 3.69, P <0.001) in rats infused with PPA on infusion days 2, 4, 5, 6, and 7 compared to PBS controls (Figure 1a). A similar pattern was observed for horizontal movement time (F (6, 126) = 2.82, P <0.001) (Figure 1f) and total distance traveled (F (6, 126) = 2.08, P <0.001) (Figure 1 g), whereby these behavioral activities were significantly higher in PPA treated animals compared to PBS controls on infusion days 2, 3, 4, 5, 6, and 7. Analysis of the number of vertical movements revealed a significant (F (6, 126) = 2.82, P <0.001) main effect of PPA treatment across infusion days, indicating PPA treated animals made more vertical movements than PBS treated animals on infusion days 3 through 7 (Figure 1b). The results of the repetitive activity measures showed significant increases in counterclockwise revolutions (F (6, 126) = 2.46, P <0.001), clockwise revolutions ( F (6, 126) = 2.40, P <0.001) and number of stereotypic movements ( F (6, 126) = 4.05, P <0.001) in PPA-treated animals across infusion days. On infusion days 3, 4, 5, 6, and 7, animals infused with PPA made more counterclockwise (Figure 1c) and clockwise (Figure 1d) revolutions than PBS controls. Stereotypy showed a similar trend whereby PPA-treated animals displayed more stereotypic movements than PBS animals on infusions days 2 through 7 (Figure 1e).

Bottom Line: Propionic acid infusions increased locomotor activity.Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species.These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Kilee Patchell-Evans Autism Research Group, Department of Psychology, University of Western Ontario, London, ON, N6A 5C2, Canada. rthoma2@uwo.ca

ABSTRACT
Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD). Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

Show MeSH
Related in: MedlinePlus