Professor of Pharmacology
University of Washington, 1975
Laboratory research projects focus on specific neural networks in the brain and their role in neurological disorders. Currently, special attention is devoted to the limbic system and the basal ganglia, with respect to glutamate and GABA-mediated influences on epileptic seizures and memory. Also under investigation are neural substrates of Parkinsonism and cocaine-induced hyperkinesias.
My co-workers and I have identified the substantia nigra as a critical site of action of GABA agonists and glutamate antagonists for protecting against experimental seizures. We have discovered a crucial site in the prepiriform cortex (named area tempestas) of the rat and monkey, from which complex partial epileptic seizures can be triggered. Our current research is aimed at determining how GABA, glutamate, serotonin, and norepinephrine interact in these brain regions to influence forebrain excitability.
In experiments, drugs are applied into discrete regions of the brain of awake animals to selectively manipulate local synaptic transmission. Acute behavioral and EEG seizure activity are evaluated, as well as short and long term molecular changes (e.g., in the expression of genes encoding neurotrophic factors) in response to seizure activity.
Related projects under development include: a) patch clamp recordings of area tempestas neurons in brain slices; b) the use of viral vectors to manipulate the genetic expression of enzymes involved in the synthesis of certain neurotransmitters in specific brain regions in vivo in an attempt to reduce seizure susceptibility; c) positron emission tomography (PET) studies of changes in regional brain metabolism during seizures; and d) determining the role of glutamate transmission in piriform cortex for recognition memory.
- DesJardin JT, Holmes AL, Forcelli PA, Cole CE, Gale JT, Wellman LL, Gale K, Malkova L: Defense-like behaviors evoked by pharmacological disinhibition of the superior colliculus in the primate. J Neurosci 33:150-155, 2013
- Dybdal D, Forcelli PA, Dubach M, Oppedisano M, Holmes A, Malkova L, Gale K: Topography of dyskinesias and torticollis evoked by inhibition of substantia nigra pars reticulata. Mov Disord Oct 31 epub, 2012
- Holmes AL, Forcelli PA, Desjardin JT, Decker AL, Teferra M, West EA, Malkova L, Gale K: Superior colliculus mediates cervical dystonia evoked by inhibition of the substantia nigra pars reticulata. J Neurosci 32:13326, 2012
- West EA, Forcelli PA, Murnen AT, McCue DL, Gale K, Malkova L. Transient inactivation of basolateral amygdala during selective satiation disrupts reinforcer devaluation in rats. Behav Neurosci 126:562, 2012
- Forcelli PA, Kozlowski R, Snyder C, Kondratyev A, Gale K. Effects of neonatal antiepileptic drug exposure on cognitive, emotional, and motor function in adult rats. J Pharmacol Exp Ther 340:558, 2012
- Forcelli PA, Kim J, Kondratyev A, Gale K. Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia 52:e207, 2011
- West EA, Desjardin JT, Gale K, Malkova L. Transient inactivation of orbitofrontal cortex blocks reinforcer devaluation in macaques. J Neurosci 31:15128-35, 2011
- Crowe SL, Tsukerman S, Gale K, Jorgensen TJ, Kondratyev AD. Phosphorylation of histone H2A.X as an early marker of neuronal endangerment following seizures in the adult rat brain. J Neurosci. 31(21):7648-56, 2011
- Forcelli PA, Gale K, Kondratyev A. Early postnatal exposure of rats to lamotrigine, but not phenytoin, reduces seizure threshold in adulthood. Epilepsia. 52:E20-2, 2011.
- Malkova L, Kozikowski AP, Gale K. The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques. Neuropharmacology60:1262, 2011
- West EA, Forcelli PA, Murnen A, Gale K, Malkova L. A visual, position-independent instrumental reinforcer devaluation task for rats. J Neurosci Methods194:297, 2011
- Besio WG, Gale KN, Medvedev AV. Possible therapeutic effects of transcutaneous electrical stimulation via concentric ring electrodes.Epilepsia.51:85-7, 2010
- Forcelli PA, Janssen MJ, Stamps LA, Sweeney C, Vicini S, Gale K. Therapeutic strategies to avoid long-term adverse outcomes of neonatal antiepileptic drug exposure. Epilepsia. 51:18-23,2010
- Kim J, Gale K, Kondratyev A. Effects of repeated minimal electroshock seizures on NGF, BDNF and FGF-2 protein in the rat brain during postnatal development. Int J Dev Neurosci. 28:227-32, 2010
- Conti G, Gale K, Kondratyev A: Immunohistochemical evaluation of the protein expression of nerve growth factor and its TrkA receptor in rat limbic regions following electroshock seizures. Neurosci Res. 2009.
- Kim JS, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia. 48:19-26, 2007
- Kim J, Kondratyev A, Gale K. Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther. 323:165-73, 2007
- Katz I, Kim J, Gale K, Kondratyev A. Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther. 322:494-500, 2007
- Wellman LL, Gale K, Malkova L. GABAA-mediated inhibition of basolateral amygdala blocks reward devaluation in macaques. J Neurosci. 25:4577-86, 2005
- Fornai F, Busceti CL, Kondratyev A, Gale K. AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus. Eur J Neurosci. 21:455-63, 2005
- Kondratyev A, Gale K. Latency to onset of status epilepticus determines molecular mechanisms of seizure-induced cell death. Brain Res Mol Brain Res. 121:86-94, 2004
- Richardson KA, Gluckman BJ, Weinstein SL, Glosch CE, Moon JB, Gwinn RP, Gale K, Schiff SJ. In Vivo Modulation of Hippocampal Epileptiform Activity with Radial Electric Fields. Epilepsia 44:768-777, 2003
- Kondratyev A, Ved R, Gale K. The effects of repeated minimal electroconvulsive shock exposure on levels of mRNA encoding fibroblast growth factor-2 and nerve growth factor in limbic regions. Neuroscience 114:411-416, 2003
- Gwinn RP, Kondratyev A, Gale K. Time-dependent increase in basic fibroblast growth factor protein in limbic regions following electroshock seizures. Neuroscience 114:403-409, 2002
- Kondratyev A, Selby D, Gale K. Status epilepticus leads to the degradation of the endogenous inhibitor of caspase-activated DNase in rats. Neurosci Lett 319:145-148, 2002
- Kondratyev A, Gale K. Temporal and spatial patterns of DNA fragmentation following focally or systemically-evoked status epilepticus in rats. Neurosci Lett. 310:13-16, 2001
- Kondratyev A, Sahibzada N, Gale K. Electroconvulsive shock exposure prevents neuronal apoptosis after kainic acid-evoked status epilepticus. Brain Res Mol Brain Res. 91:1-13, 2001
- Dybdal D, Gale K. Postural and anticonvulsant effects of inhibition of the rat subthalamic nucleus. J Neurosci. 20:6728-33, 2000
- Doherty J, Gale K, Eagles DA. Evoked epileptiform discharges in the rat anterior piriform cortex: generation and local propagation. Brain Res.
- Kondratyev A, Gale K. Intracerebral injection of caspase-3 inhibitor prevents neuronal apoptosis after kainic acid-evoked status epilepticus. Brain Res Mol Brain Res. 75:216-24, 2000
- Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia. 40:1051-7, 1999
- Masco D, Sahibzada N, Switzer R, Gale K. Electroshock seizures protect against apoptotic hippocampal cell death induced by adrenalectomy. Neurosciencee.
- New KC, Gale K, Martuza RL, Rabkin SD. Novel synthesis and release of GABA in cerebellar granule cell cultures after infection with defective herpes simplex virus vectors expressing glutamic acid decarboxylase. Brain Res Mol Brain Res. 61:121-35, 1998
- Cassidy RM, Gale K. Mediodorsal thalamus plays a critical role in the development of limbic motor seizures. J Neurosci. 18:9002-9, 1998
- Tortorella A, Halonen T, Sahibzada N, Gale K. A crucial role of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures. J Pharmacol Exp Ther. 280:1401-5, 1997