Just Accepted by International Journal of Neuroscience
Up-Regulated Cytoplasmic FMRP-interacting protein 1 in Intractable Temporal Lobe Epilepsy Patients and a Rat Model Yunyi Huang, Yangmei Chen doi:10.3109/00207454.2015.1038711
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
Abstract Cytoplasmic FMRP-interacting protein 1 (CYFIP1) is a multifunctional protein which expresses highly at excitatory synapses and can locally regulate actin cytoskeletal dynamics, spine morphology and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion . Altered synaptic actin plays a role in the pathogenesis of epilepsy. The aim of this study was to investigate the expression pattern of CYFIP1 in temporal lobe epilepsy (TLE). Protein and mRNA expression levels were compared in temporal lobe tissue from patients with TLE versus trauma patients without TLE using quantitative real-time PCR (qRT-PCR), double-label immunofluorescence and Western blot analysis. We have further determined the expression pattern of Cyfip1 mRNA and protein in the hippocampus and adjacent cortex of a common rat model of TLE, lithium-pilocarpine treatment, compared to control rats. CYFIP1 expression was significantly upregulated in the temporal neocortex of patients with intractable TLE and pilocarpine-treated rats compared to control groups. CYFIP1 localizes to the cytoplasm of neurons, and is not expressed in the astrocytes. Furthermore, CYFIP1 expression levels increased significantly in the 2 months after pilocarpine treatment, which corresponds to the period of epileptogenesis. Thus, our results indicate that CYFIP1 may be involved in the pathogenesis of TLE.
© 2015 Informa Healthcare USA, Inc. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Publisher: Taylor & Francis Journal: International Journal of Neuroscience DOI: http://dx.doi.org/10.3109/00207454.2015.1038711
Up-Regulated Cytoplasmic FMRP-interacting protein 1 in Intractable Temporal Lobe
TE D
Title:
Author: Yunyi Huang
Medical University
Department of Neurology, The second Affiliated Hospital, Chongqing
C EP
Institutional Affiliation:
Corresponding Author Name: Yangmei Chen Address: 74 Lin Jiang Road, Chongqing, China
AC
Telephone: +86-13608348562 E-mail: [email protected] Abstract
ST
Cytoplasmic FMRP-interacting protein 1 (CYFIP1) is a multifunctional protein which
expresses highly at excitatory synapses and can locally regulate actin cytoskeletal dynamics, spine morphology and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
JU
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
Epilepsy Patients and a Rat Model
receptor lateral diffusion . Altered synaptic actin plays a role in the pathogenesis of epilepsy. The aim of this study was to investigate the expression pattern of CYFIP1 in temporal lobe epilepsy (TLE). Protein and mRNA expression levels were compared in temporal lobe tissue from patients
with TLE versus trauma patients without TLE using quantitative real-time PCR (qRT-PCR), double-label immunofluorescence and Western blot analysis. We have further determined the expression pattern of Cyfip1 mRNA and protein in the hippocampus and adjacent cortex of a 1
common rat model of TLE, lithium-pilocarpine treatment, compared to control rats. CYFIP1 expression was significantly upregulated in the temporal neocortex of patients with intractable TLE and pilocarpine-treated rats compared to control groups. CYFIP1 localizes to the cytoplasm of
TE D
neurons, and is not expressed in the astrocytes. Furthermore, CYFIP1 expression levels increased significantly in the 2 months after pilocarpine treatment, which corresponds to the period of
TLE. Synaptic plasticity
actin cytoskeleton
ST
AC
C EP
Keywords CYFIP1 Temporal lobe epilepsy
JU
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
epileptogenesis. Thus, our results indicate that CYFIP1 may be involved in the pathogenesis of
2
Introduction Epilepsy is a chronic condition or a group of chronic condition characterized by recurrent unprovoked seizures and is the second most common neurological disorder following stroke [1].
TE D
There is currently no specific drug for curing or preventing epilepsy [2]. Temporal lobe epilepsy (TLE), a common form of focal epilepsy, is often resistant to antiepileptic drugs (AEDs) [3]. Clinical
neuropathological changes including hippocampal cell loss, mossy fiber sprouting, reactive gliosis,
C EP
ectopic granule cells, dentate granule cell dispersion, and hyperexcitable networks have been
identified both in humans [4-7] and experimental animals [8]. Although, people have detected aberrant expression of synaptosomal proteins, cytoskeleton proteins and neurotransmitter
AC
receptors in the hippocampus of humans with TLE [9-12], it remains unclear how pathological progress in epilepsy might be triggered by changes at the molecular and cellular levels. Cytoplasmic FMRP-interacting protein 1 (CYFIP1), also known as ‘‘specific Rac1-activated’’
ST
(SRA1) protein [13], is a key functional partner of Fragile X mental retardation protein (FMRP) [14-16]. CYFIP1 is localized on the 15q11.2 region of the human genome which has been
implicated in the development of neurological and neuropsychiatric conditions such as autism
JU
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
and experimental evidence have emphasized the major role of the hippocampus in TLE. Moreover,
spectrum disorder, epilepsy, intellectual disability and schizophrenia [17-24]. Moreover, CYFIP1 is highly expressed at excitatory synapses and can locally regulate actin cytoskeletal dynamics in the postsynaptic domain [25]. Based on the known functions of CYFIP1, we hypothesized that this protein may play a role in the pathogenesis of TLE. Here, we investigated whether CYFIP1 mRNA and protein expression is altered in tissue samples from human patients with intractable TLE using immunofluorescence, 3
qRT-PCR and Western blotting. We further investigated the change in levels of CYFIP1 mRNA and protein in the hippocampus of a rat model of TLE at different time points following the initiating brain damage, lithium chloride-pilocarpine-induced status epilepticus (SE).
Demographic and Clinical Characteristics of the Epilepsy Subjects
TE D
Results
the mean course of these patients was 11.45±4.92 years. The control group had a mean age of
C EP
30.30±12.95 years with 15 men and 5 women. There were no significant statistical differences in age and sex between the TLE group and control group (P
Up-Regulated Cytoplasmic FMRP-interacting protein 1 in Intractable Temporal Lobe Epilepsy Patients and a Rat Model Yunyi Huang, Yangmei Chen doi:10.3109/00207454.2015.1038711
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
Abstract Cytoplasmic FMRP-interacting protein 1 (CYFIP1) is a multifunctional protein which expresses highly at excitatory synapses and can locally regulate actin cytoskeletal dynamics, spine morphology and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion . Altered synaptic actin plays a role in the pathogenesis of epilepsy. The aim of this study was to investigate the expression pattern of CYFIP1 in temporal lobe epilepsy (TLE). Protein and mRNA expression levels were compared in temporal lobe tissue from patients with TLE versus trauma patients without TLE using quantitative real-time PCR (qRT-PCR), double-label immunofluorescence and Western blot analysis. We have further determined the expression pattern of Cyfip1 mRNA and protein in the hippocampus and adjacent cortex of a common rat model of TLE, lithium-pilocarpine treatment, compared to control rats. CYFIP1 expression was significantly upregulated in the temporal neocortex of patients with intractable TLE and pilocarpine-treated rats compared to control groups. CYFIP1 localizes to the cytoplasm of neurons, and is not expressed in the astrocytes. Furthermore, CYFIP1 expression levels increased significantly in the 2 months after pilocarpine treatment, which corresponds to the period of epileptogenesis. Thus, our results indicate that CYFIP1 may be involved in the pathogenesis of TLE.
© 2015 Informa Healthcare USA, Inc. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Publisher: Taylor & Francis Journal: International Journal of Neuroscience DOI: http://dx.doi.org/10.3109/00207454.2015.1038711
Up-Regulated Cytoplasmic FMRP-interacting protein 1 in Intractable Temporal Lobe
TE D
Title:
Author: Yunyi Huang
Medical University
Department of Neurology, The second Affiliated Hospital, Chongqing
C EP
Institutional Affiliation:
Corresponding Author Name: Yangmei Chen Address: 74 Lin Jiang Road, Chongqing, China
AC
Telephone: +86-13608348562 E-mail: [email protected] Abstract
ST
Cytoplasmic FMRP-interacting protein 1 (CYFIP1) is a multifunctional protein which
expresses highly at excitatory synapses and can locally regulate actin cytoskeletal dynamics, spine morphology and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
JU
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
Epilepsy Patients and a Rat Model
receptor lateral diffusion . Altered synaptic actin plays a role in the pathogenesis of epilepsy. The aim of this study was to investigate the expression pattern of CYFIP1 in temporal lobe epilepsy (TLE). Protein and mRNA expression levels were compared in temporal lobe tissue from patients
with TLE versus trauma patients without TLE using quantitative real-time PCR (qRT-PCR), double-label immunofluorescence and Western blot analysis. We have further determined the expression pattern of Cyfip1 mRNA and protein in the hippocampus and adjacent cortex of a 1
common rat model of TLE, lithium-pilocarpine treatment, compared to control rats. CYFIP1 expression was significantly upregulated in the temporal neocortex of patients with intractable TLE and pilocarpine-treated rats compared to control groups. CYFIP1 localizes to the cytoplasm of
TE D
neurons, and is not expressed in the astrocytes. Furthermore, CYFIP1 expression levels increased significantly in the 2 months after pilocarpine treatment, which corresponds to the period of
TLE. Synaptic plasticity
actin cytoskeleton
ST
AC
C EP
Keywords CYFIP1 Temporal lobe epilepsy
JU
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
epileptogenesis. Thus, our results indicate that CYFIP1 may be involved in the pathogenesis of
2
Introduction Epilepsy is a chronic condition or a group of chronic condition characterized by recurrent unprovoked seizures and is the second most common neurological disorder following stroke [1].
TE D
There is currently no specific drug for curing or preventing epilepsy [2]. Temporal lobe epilepsy (TLE), a common form of focal epilepsy, is often resistant to antiepileptic drugs (AEDs) [3]. Clinical
neuropathological changes including hippocampal cell loss, mossy fiber sprouting, reactive gliosis,
C EP
ectopic granule cells, dentate granule cell dispersion, and hyperexcitable networks have been
identified both in humans [4-7] and experimental animals [8]. Although, people have detected aberrant expression of synaptosomal proteins, cytoskeleton proteins and neurotransmitter
AC
receptors in the hippocampus of humans with TLE [9-12], it remains unclear how pathological progress in epilepsy might be triggered by changes at the molecular and cellular levels. Cytoplasmic FMRP-interacting protein 1 (CYFIP1), also known as ‘‘specific Rac1-activated’’
ST
(SRA1) protein [13], is a key functional partner of Fragile X mental retardation protein (FMRP) [14-16]. CYFIP1 is localized on the 15q11.2 region of the human genome which has been
implicated in the development of neurological and neuropsychiatric conditions such as autism
JU
Int J Neurosci Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 06/28/15 For personal use only.
and experimental evidence have emphasized the major role of the hippocampus in TLE. Moreover,
spectrum disorder, epilepsy, intellectual disability and schizophrenia [17-24]. Moreover, CYFIP1 is highly expressed at excitatory synapses and can locally regulate actin cytoskeletal dynamics in the postsynaptic domain [25]. Based on the known functions of CYFIP1, we hypothesized that this protein may play a role in the pathogenesis of TLE. Here, we investigated whether CYFIP1 mRNA and protein expression is altered in tissue samples from human patients with intractable TLE using immunofluorescence, 3
qRT-PCR and Western blotting. We further investigated the change in levels of CYFIP1 mRNA and protein in the hippocampus of a rat model of TLE at different time points following the initiating brain damage, lithium chloride-pilocarpine-induced status epilepticus (SE).
Demographic and Clinical Characteristics of the Epilepsy Subjects
TE D
Results
the mean course of these patients was 11.45±4.92 years. The control group had a mean age of
C EP
30.30±12.95 years with 15 men and 5 women. There were no significant statistical differences in age and sex between the TLE group and control group (P
