Impaired ILK function is associated with deficits in hippocampal based memory and synaptic plasticity in a FASD rat model

D. Bhattacharya, E. P. Dunaway, S. Bhattacharya, J. Bloemer, M. Buabeid, M. Escobar, V. Suppiramaniam, M. Dhanasekaran

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Abstract

Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term that encompasses a wide range of anatomical and behavioral problems in children who are exposed to alcohol during the prenatal period. There is no effective treatment for FASD, because of lack of complete characterization of the cellular and molecular mechanisms underlying this condition. Alcohol has been previously characterized to affect integrins and growth factor signaling receptors. Integrin Linked Kinase (ILK) is an effector of integrin and growth-factor signaling which regulates various signaling processes. In FASD, a downstream effector of ILK, Glycogen Synthase Kinase 3β (GSK3β) remains highly active (reduced Ser9 phosphorylation). GSK3β has been known to modulate glutamate receptor trafficking and channel properties. Therefore, we hypothesize that the cognitive deficits accompanying FASD are associated with impairments in the ILK signaling pathway. Pregnant Sprague Dawley rats consumed a "moderate" amount of alcohol throughout gestation, or a calorie-equivalent sucrose solution. Contextual fear conditioning was used to evaluate memory performance in 32-33-dayold pups. Synaptic plasticity was assessed in the Schaffer Collateral pathway, and hippocampal protein lysates were used to evaluate ILK signaling. Alcohol exposed pups showed impaired contextual fear conditioning, as compared to control pups. This reduced memory performance was consistent with decrease in LTP as compared to controls. Hippocampal ILK activity and GSK3β Ser21/9 phosphorylation were significantly lower in alcohol-exposed pups than controls. Increased synaptic expression of GluR2 AMPA receptors was observed with immunoprecipitation of post-synaptic density protein 95 (PSD95). Furthermore, immunoprecipitation of ILK revealed a decreased interaction with GluR2. The ILK pathway appears to play a significant role in memory and synaptic plasticity impairments in FASD rats. These impairments appear to be mediated by reduced GSK3β regulation and increased synaptic stabilization of the calcium-impermeable GluR2 AMPA receptors.

Original languageEnglish
Article numbere0135700
JournalPLoS ONE
Volume10
Issue number8
DOIs
Publication statusPublished - 25 Aug 2015

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fetal alcohol syndrome
Fetal Alcohol Spectrum Disorders
Neuronal Plasticity
integrins
Plasticity
Rats
phosphotransferases (kinases)
Glycogen Synthase Kinase 3
animal models
Alcohols
Data storage equipment
alcohols
pups
AMPA Receptors
Immunoprecipitation
Integrins
Fear
conditioned behavior
Phosphorylation
fearfulness

Cite this

Bhattacharya, D., Dunaway, E. P., Bhattacharya, S., Bloemer, J., Buabeid, M., Escobar, M., ... Dhanasekaran, M. (2015). Impaired ILK function is associated with deficits in hippocampal based memory and synaptic plasticity in a FASD rat model. PLoS ONE, 10(8), [e0135700]. https://doi.org/10.1371/journal.pone.0135700
Bhattacharya, D. ; Dunaway, E. P. ; Bhattacharya, S. ; Bloemer, J. ; Buabeid, M. ; Escobar, M. ; Suppiramaniam, V. ; Dhanasekaran, M. / Impaired ILK function is associated with deficits in hippocampal based memory and synaptic plasticity in a FASD rat model. In: PLoS ONE. 2015 ; Vol. 10, No. 8.
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abstract = "Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term that encompasses a wide range of anatomical and behavioral problems in children who are exposed to alcohol during the prenatal period. There is no effective treatment for FASD, because of lack of complete characterization of the cellular and molecular mechanisms underlying this condition. Alcohol has been previously characterized to affect integrins and growth factor signaling receptors. Integrin Linked Kinase (ILK) is an effector of integrin and growth-factor signaling which regulates various signaling processes. In FASD, a downstream effector of ILK, Glycogen Synthase Kinase 3β (GSK3β) remains highly active (reduced Ser9 phosphorylation). GSK3β has been known to modulate glutamate receptor trafficking and channel properties. Therefore, we hypothesize that the cognitive deficits accompanying FASD are associated with impairments in the ILK signaling pathway. Pregnant Sprague Dawley rats consumed a {"}moderate{"} amount of alcohol throughout gestation, or a calorie-equivalent sucrose solution. Contextual fear conditioning was used to evaluate memory performance in 32-33-dayold pups. Synaptic plasticity was assessed in the Schaffer Collateral pathway, and hippocampal protein lysates were used to evaluate ILK signaling. Alcohol exposed pups showed impaired contextual fear conditioning, as compared to control pups. This reduced memory performance was consistent with decrease in LTP as compared to controls. Hippocampal ILK activity and GSK3β Ser21/9 phosphorylation were significantly lower in alcohol-exposed pups than controls. Increased synaptic expression of GluR2 AMPA receptors was observed with immunoprecipitation of post-synaptic density protein 95 (PSD95). Furthermore, immunoprecipitation of ILK revealed a decreased interaction with GluR2. The ILK pathway appears to play a significant role in memory and synaptic plasticity impairments in FASD rats. These impairments appear to be mediated by reduced GSK3β regulation and increased synaptic stabilization of the calcium-impermeable GluR2 AMPA receptors.",
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Bhattacharya, D, Dunaway, EP, Bhattacharya, S, Bloemer, J, Buabeid, M, Escobar, M, Suppiramaniam, V & Dhanasekaran, M 2015, 'Impaired ILK function is associated with deficits in hippocampal based memory and synaptic plasticity in a FASD rat model', PLoS ONE, vol. 10, no. 8, e0135700. https://doi.org/10.1371/journal.pone.0135700

Impaired ILK function is associated with deficits in hippocampal based memory and synaptic plasticity in a FASD rat model. / Bhattacharya, D.; Dunaway, E. P.; Bhattacharya, S.; Bloemer, J.; Buabeid, M.; Escobar, M.; Suppiramaniam, V.; Dhanasekaran, M.

In: PLoS ONE, Vol. 10, No. 8, e0135700, 25.08.2015.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bhattacharya, D.

AU - Dunaway, E. P.

AU - Bhattacharya, S.

AU - Bloemer, J.

AU - Buabeid, M.

AU - Escobar, M.

AU - Suppiramaniam, V.

AU - Dhanasekaran, M.

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