RESEARCH SUMMARY

My lab uses electrophysiological techniques with brain slices and immortalized cultured cells to study the tuning of inhibitory neurotransmission during normal brain function and in disease states, including epilepsy. GABA is the primary inhibitory neurotransmitter in the adult brain and is critical for normal brain function. However, in the developing brain, GABA acts as an excitatory signal that directs normal neuronal migration and synaptogenesis. We have found that a predominant GABA receptor expressed primarily during early life is subject to RNA editing in a developmentally regulated fashion. By introducing a single amino acid change in a key portion of these GABA receptors, RNA editing leads to significant changes in receptor function, thereby producing a brief window in late embryogenesis/early postnatal life in which GABA causes the prolonged/slow depolarizations that are important for the subsequent formation of both excitatory and inhibitory connections later in life.
Lagrange's clinical interest is in the treatment of women with epilepsy. It has been known for a few years that some of the medications used to treat epilepsy may increase the risk of having a child with congenital malformations. Unfortunately, these teratogenic drugs are also widely used for a number of other neurological and psychiatric disorders, such as migraines and bipolar disorder. Alarmingly, recent work has suggested that children exposed to a subset of these drugs in utero have reduced IQ later in life, and an increased incidence of neurodevelopmental disorders such as autism. Further animal work has suggested that these poor cognitive outcomes may involve subtle cortical malformation/laminar disruption, which are thought to be mediated by the GABA modulatory nature of these drugs. Lagrange's lab is working to understand the role of specific GABA receptors in brain development and how these processes are regulated during normal development, as well as how they may be disrupted by disease states and medications.

RECENT PUBLICATIONS

1. The Potency of µ-Opioid Hyperpolarization of Hypothalamic Arcuate Neurons is Rapidly Attenuated by 17 -Estradiol. AH Lagrange, et l J Neurosci 14:6196-6204, 1994.
2. Tolerance in Hypothalamic beta-Endorphin Neurons Following Chronic Morphine. MJ Kelly, G. Zhang, AH Lagrange, OK Rönnekleiv Regulatory Peptides (Suppl) 54:145-146, 1994.
3. Estradiol-17 and Opioid Peptides Rapidly Hyperpolarize GnRH Neurons: A Cellular Mechanism of Negative Feedback? AH Lagrange, et al; Endocrinology (Rapid Commun) 136:2341-2344, 1995.
4. Estrogen Rapidly Uncouples µ-Opioid Receptors from Potassium channels via Activation of Protein Kinase A MJ Kelly, AH Lagrange, OK Rönnekleiv; Analgesia 1:494-497, 1995.
5. Tolerance of Hypothalamic Beta-Endorphin Neurons to µ-Opioid Receptor Activation Following Chronic Morphine. G. Zhang, AH Lagrange OK Rönnekleiv, MJ Kelly; J Pharm Exp Ther 277:551-558, 1996.
6. Estrogen Rapidly Attenuates a GABAB Response in Hypothalamic Neurons. AH Lagrange, et al; Neuroendocrinology 64:114-123, 1996.
7. Tolerance to µ-Opioid Receptor Agonists but Not Cross-Tolerance to GABAB Receptor Agonists in Arcuate A12 Dopamine Neurons With Chronic Morphine Treatment EJ Wagner, G. Zhang, AH Lagrange, OK Rönnekleiv, MJ Kelly; J Pharm Exp Ther 280:1057-1064, 1997.
8. Modulation of G Protein-Coupled Receptors by an Estrogen Receptor that Activates Protein Kinase A. AH Lagrange, et al . Mol. Pharm. 51(4):605-12, 1997.
9. Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways MJ Kelly, AH Lagrange, EJ Wagner, OK Ronnekleiv; Steroids 64:64-75 1999.
10. Estrogen modulation of K(+) channel activity in hypothalamic neurons involved in the control of the reproductive axis. MJ Kelly, OK Ronnekleiv, N. Ibrahim, AH Lagrange, EJ Wagner . Steroids 67:447-56 2002
11. Rasmussen’s syndrome and new-onset narcolepsy, cataplexy and epilepsy in an adult. AH Lagrange et al Epilepsy and Behavior 4:788-792 2003
12. Mutations in the GABRA1 and EFHC1 genes are rare in autosomal dominant juvenile myoclonic epilepsy. S. Ma, M. A. Blair, B. Abou-Khalil, AH Lagrange, C.A. Gurnett, P. Hedera Epilepsy Research 71:129-134. 2006
13. Rhythmic Ictal Non-Clonic Hand (RINCH) Motions: a Distinct Contralateral Sign in Temporal Lobe Epilepsy Associated with Dystonic Posturing. G. R. Lee, A. Arain, N. Lim, A Lagrange, P. Singh, B. Abou-Khalil. Epilepsia 47(12):2189-2192 2006.
14. Occult Celiac Disease Presenting As Epilepsy And MRI Changes That Responded To Gluten Free Diet. L. Harper, H. Moses, and AH Lagrange Neurology 68(7):533-4 2007.
15. Enhanced Desensitization In GABAA Receptors Containing The ?-4 Subunit. AH Lagrange, EJ Botzolakis, RL Macdonald J Physiol 578:655-76 2007.
16. Developmental modulation of GABA(A) receptor function by RNA editing (Brief Communication) Elizabeth Y. Rula, AH Lagrange M. M. Jacobs, NingNing Hu, RL Macdonald and R.B. Emeson. J Neurosci 28:6196-6201 2008
17. Transitional Sharp Wave at Ictal Onset- A Neocortical Ictal Pattern. NJ Azar, AH Lagrange, BW Abou-Khalil Clin Neurophys 120:665-672 2009.
18. Achieving Synaptically Relevant Pulses of Neurotransmitter Using PDMS Microfluidics. E.J Botzolakis, A. Maheshwari, HJ Feng, AH Lagrange, JH Shaver, NJ Kassebaum, R. Venkataraman, FJ Baudenbacher, RL Macdonald, J Neurosci Methods 177:294-302 2008.
19. Benzodiazepine modulation of GABA(A) receptor opening frequency depends on activation context: A patch clamp and simulation study. MT Bianchi, EJ Botzolakis, AH Lagrange RL Macdonald Epilepsy Res (In Press) 2009
20. Generalized-Onset Seizures With Secondary Focal Evolution. R. Williamson, S. Hanif, GC Mathews, AH Lagrange, BW Abou-Khalil Epilepsia 50: 1837-1832. 2009.

Invited Reviews, Commentaries and Book Chapters

1. Congenital defects of the scalp and skull, J.H. Piatt Jr, AH Lagrange, A.L. Albright, I.F. Pollack, P.D. Adelson (eds): Principles and Practice of Pediatric Neurosurgery. New York, NY, Thieme, p 209-218. 1998
2. Nontranscriptional Effects of Estradiol in Neuropeptide Neurons, MJ Kelly, AH Lagrange Curr. Opin. Endo.and Diab 5:66 72. 1998.
3. Neuroactive Steroids AH Lagrange and MJ Kelly in H.L Henry and A.W. Norman (eds) Encyclopedia of Hormones Academic Press p8-19, 2004
4. GABA Receptors Gone Bad: The Wrong Place at the Wrong Time AH Lagrange Epilepsy Currents 5:91-95 2005
5. Retigabine: Bending Potassium Channels To Our Will Lagrange AH Lagrange Epilepsy Currents 5:166-69. 2005
6. Dancing the delta shuffle: Neurosteroids Regulate GABAA Receptor Expression. AH Lagrange Epilepsy Currents 6(1):14-17, 2006.
7. Genetic Variants In Absence Epilepsy: A Contextual Consideration Of Calcium Current Kinetics. AH Lagrange Epilepsy Currents 6(3):12-14, 2006.
8. Valproate Enhances Neuropeptide Y Expression: Modulating the Modulator. AH Lagrange Epilepsy Currents 7(2):23-5 2007.
9. Pregnancy and Seizure Mediations. Hallway Conversations at Epilepsy.Com 2007
10.. Folic acid supplementation for women with epilepsy who might become pregnant. AH Lagrange. Nature Clinical Practice Neurol 5(1):16-17, 2009.
11. Feeling Out the Elephant in the Room: Why Do Temporal Lobe Seizures Cause Unconsciousness? AH Lagrange Epilepsy Curr (In Press), 2009.

CONTACT INFORMATION

Department of Neurology, Vanderbilt University
6144 Medical Research Building III
Nashville, TN 37232-8552
Office: (615) 322-5979
E-mail: andre.lagrange@vanderbilt.edu

     
 
     

Faculty>
Andre Lagrange, Ph.D., M.D., Assistant Professor of Neurology

BIOGRAPHICAL SKETCH

Dr. Lagrange earned B.S. degrees is both Chemistry and Biology (with Honors) at the University of Washington in 1987. He earned a Ph.D. in Physiology and Pharmacology in 1996 and a M.D. in 1997, both at the Oregon Health Sciences University, while supported by a NIMH pre-doctoral NRSA fellowship. The next year he did an internal medicine internship at Saint Joseph Mercy Hospital in Ann Arbor, MI, followed by Neurology residency (1998-2001) and Clinical Neurophysiology Fellowship (2001-02) at the University of Michigan, Ann Arbor.

Dr. Lagrange was named Assistant Professor of Neurology at Vanderbilt University in 2002. In addition to his laboratory and clinical research activities, Dr. Lagrange is involved in the teaching and mentoring of residents, fellows, graduate and undergraduate students, and also serves as ad hoc reviewer for Epilepsy Research and Neuropharmacology. Dr. Lagrange’s honors include being the past recipient of a William Penry Epilepsy Minifellowship (2000) and the American Academy of Neurology Residents Scholarship (2001).


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