Research Summary

Research in my lab focuses on understanding how neuronal networks are developed and maintained in the brain, with the goal of applying this knowledge to the development of therapeutics for neurodevelopmental and neurodegenerative diseases. We utilize new molecular approaches in neuroscience and mouse genetics to conduct research on the molecular basis of neurologic diseases. In particular, we are interested in molecular and cellular mechanisms that govern the synapse formation and plasticity in the brain areas that play a critical role in learning and memory.

Three main research areas in the lab include studies on (1) the mechanisms underlying the pathophysiology of Fragile X Syndrome (FXS); (2) glial control of injury-induced synapse remodeling in the brain following traumatic brain injury (TBI); (3) role of actin-regulating proteins in synaptic plasticity, Aβ-induced synapse loss and cognitive decline associated with AD.

(1) The mechanisms underlying the pathophysiology of Fragile X Syndrome (FXS)

My lab discovered the role of MMP9 in pathophysiology of FXS and demonstrated beneficial effects of minocycline on synapse development and behavioral performance in an animal model of FXS (Bilousova et al., 2009; Rotschafer et al., 2012; Dansie et al., 2013; Sidhu et al., 2014). These findings prompted several clinical trials that tested the effects of minocycline treatment in patients with FXS (Paribello et al., 2010; Utari et al., 2010). Ongoing studies focus on the role of MMP9 and extracellular matrix in autistic behaviors associated with FXS, including the mechanisms of auditory hypersensitivity. In collaboration with Drs. Binder and Razak we are working to develop a preclinical model of auditory processing deficits in FXS to determine the interactions between structural and functional changes in auditory circuits in Fragile X mice and to generate therapeutic ideas by targeting multiple pathways involved in the pathophysiology of FXS.

Bilousova T, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW and Ethell IM. 2009. Minocycline Promotes Dendritic Spine Maturation and Improves Behavioral Performance in the Fragile X Mouse Model. J Med Gen., 46(2):94-102.

Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, Ethell DW. 2010. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. Oct 11: p10:91.

Utari, A, Chonchaiya, W, Rivera, SM, Schneider, A, Hagerman, RJ, Faradz, SM, Ethell, IM, Nguyen, DV 2010. Side effects of minocycline treatment in patients with fragile x syndrome and exploration of outcome measures. Am J Intellect Dev Disabil. Vol. 115(5): p433-443.

Rotschafer SE, Trujillo MS, Dansie LE, Ethell IM, Razak KA. 2012. Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of Fragile X Syndrome. Brain Res., 1439:7-14. Epub 2011 Dec 31.

Dansie LE, Phommahaxay K, Okusanya AG, Uwadia J, Huang M, Rotschafer SE, Razak KA, Ethell DW and Ethell IM. 2013. Long-lasting Effects of Minocycline on Behavior in Young but not Adult Fragile X Mice. Neuroscience. 246:186-198.

Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. 2014. Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model. J Neuroscience. 34 (30):9867-9879.

(2) Glial control of synapse development and injury-induced synapse remodeling following traumatic brain injury (TBI).

We were first to demonstrate the importance of Eph/ephrin interactions in dendritic spine/synapse formation (Ethell et al., 2001; Henkemeyer et al., 2003). We were able to show that hippocampal neurons lacking multiple EphB receptors develop abnormal spines in vivo, whereas the EphB receptor activation in neurons induced dendritic spine maturation (Henkemeyer et al., 2003). Our new studies also suggest that ephrin-B/EphB receptor signaling is involved in astrocyte-mediated synapse development and remodeling triggered by TBI (Koeppen et al., 2014). While considerable efforts were devoted to the treatments that enhance neuron survival following brain injury, our understanding of the mechanisms that regulate injury-induced brain rewiring is limited. Brain injury can cause dramatic changes in synaptic connectivity in the brain may lead to cognitive and neuropsychological changes that persist for decades. In the ongoing studies, we investigate new mechanisms of astrocyte-mediated remodeling of synaptic connections in the brain that may aid the functional brain recovery after brain injury. The collaborative studies with Dr. Andre Obenaus’s laboratory at the Loma Linda University we are investigating whether the regulation of ephrin-B levels in reactive astrocytes plays a protective or destructive role in the recovery after TBI using both genetic and pharmacologic approaches in a combination with biochemical, anatomical, electophysiological methods and non-invasive MRI imaging.

Ethell IM, Irie F, Kalo MS, Couchman JR, Pasquale EB and Yamaguchi Y. 2001. EphB2/syndecan-2 signaling in dendritic spine morphogenesis. Neuron, 31: 1001-1013.

Henkemeyer M, Itkis OS, Ngo M, Hickmott PW and Ethell IM. 2003. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol., 163(6):1313-1326.

Moeller ML, Shi Y, Reichardt LF and Ethell IM 2006. EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of FAK and RhoA activation. J Biol Chem. 281(3):1587-98. Epub 2005 Nov 18.

Shi Y and Ethell IM. 2006. Integrins Control Dendritic Spine Plasticity in Hippocampal Neurons through NMDA Receptor and CaMKII-Mediated Actin Reorganization. J. Neurosci. 26(6):1813-1822.

Cesa R, Premoselli F, Renna A, Ethell IM, Pasquale EB, Strata P. 2011. Eph receptors are involved in the activity-dependent synaptic wiring in the mouse cerebellar cortex. PLoS One. 6(4):e19160.

Koeppen J, Nikolakopoulou AM, Garcia M, Leish J, Obenaus A and Ethell IM. Targeting ephrin-B1 signaling in astrocytes to regulate synapse development and remodeling following traumatic brain injury. 2014. CSH meeting on Glia in Health and Diseases.

(3) Role of actin-regulating protein cofilin in synaptic plasticity plasticity.

Our studies demonstrated that EphB receptors can induce cofilin dephosphorylation and activation, which underlies NMDAR-mediated dendritic spine/synapse remodeling (Shi et al., 2009). Using both in vitro and in vivo systems in combination with biochemical, anatomical and electrophysiological studies, we were able to show that NMDAR spatially controls cofilin activity in dendritic spines. This study also led to an interesting discovery that in addition to phosphorylation state, NMDA-induced cofilin translocation into dendritic spines is also regulated by scaffolding protein β-arrestin. We showed that NMDA-induced cofilin translocation to spines and spine remodeling are impaired in β-arrestin2 KO neurons, suggesting that β-arrestin2 may play important role in the regulation of NMDA-dependent plasticity through special control over cofilin activity (Pontrello et al., 2012). Our findings also suggest that a spatial regulation of actin in dendritic spines, post-synaptic sites, may play a role in Aβ-mediated spine loss associated with Alzheimer’s disease (AD), and may contribute to impaired learning and memory that are seen during early stages of AD (Pontrello et al., 2012). Our future studies will establish the role of β-arrestin-2 in Aβ-induced loss of synapses, impaired synaptic plasticity and cognitive decline in a mouse model of AD.

Shi Y, C. Pontrello, K. Defea, L.F. Reichardt and I. M. Ethell 2009. Focal adhesion kinase acts downstream of EphB receptors to maintain mature dendritic spines by regulating cofilin activity. J. Neurosci., 29(25): 8075-8086.

Pontrello C and Ethell IM 2009. Accelerators, brakes, and gears of actin dynamics in dendritic spines. TONJ, 3: 67-86.

Pontrello CG, Sun M-Y, Lin A, Fiacco TA, DeFea KA, and Ethell IM. 2012. Cofilin under control of β-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning. PNAS, 109(7):E442-451.



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