Carolyn R. Houser, Ph.D.

Work Address:
CHS
Los Angeles, CA 90095 CHS
Los Angeles, CA 90095

Affiliations
Affiliations
Professor, Neurobiology
Member, Brain Research Institute, Neuroscience GPB Home Area
Research Interests
Much of the work in our laboratory is focused on identifying morphological changes that may contribute to the development of epilepsy. In epilepsy, neurons in some specific regions of the brain, such as the hippocampus, become hyperexcitable and begin to be activated or fire in synchrony, thus producing spontaneous seizures or epilepsy. One of the major causes of epilepsy appears to be damage to the brain through severe, prolonged seizures or head trauma early in life. It then requires some time for spontaneous seizures to develop. Our goal is to identify the anatomical and neurochemical changes that occur between the initial insult and the subsequent development of epilepsy. Our broad hypothesis is that progressive changes in the GABA system, a major neurotransmitter system that normally helps inhibit or control excessive neuronal activity in the brain, are critical for the development of epilepsy. By studying brain tissue from animal models of epilepsy and human tissue from patients with temporal lobe epilepsy, we have identified several interesting changes that could contribute to the development of seizure activity. We are pursuing these findings through immunohistochemical and biochemical studies of the hippocampus. First, some but not all neurons that use GABA as their neurotransmitter are damaged in epilepsy. We are attempting to determine why some GABA neurons are easily damaged while others are spared. Since some GABA neurons remain, we are studying the changes that occur in these neurons to determine if there is reorganization of their axons and synapses with other neurons. Finally, we are studying changes in the receptors through which GABA influences the activity of other neurons. Recently, in a mouse model of temporal lobe epilepsy, we have found that some specific subunits of GABA-A receptors are altered in ways that could contribute to seizure activity. More detailed knowledge of such changes could lead to the development of new pharmacological methods for treating existing epilepsy, and, ultimately, preventing the development of this disorder.
Biography

Research Interest: Neurochemical anatomy, neuronal plasticity and development of the CNS

The broad research interests of the laboratory are the neurochemical anatomy and morphological plasticity of the mammalian central nervous system. Research is focused on the gamma-aminobutyric acid (GABA) system. GABA is an extremely important neurotransmitter in many brain regions and may also have trophic roles during development of the nervous system. Both the presynaptic neurons that use GABA as a neurotransmitter and the postsynaptic sites at which these neurons exert their influence are being studied. Immunohistochemical and in situ hybridization methods are used to study the localization and regulation of the proteins and mRNAs of two forms of the synthesizing enzyme for GABA, glutamic acid decarboxylase (GAD) and multiple subtypes of the GABA-A receptor. Interrelationships between the GABA neurons and their receptors are being studied in the normal brain, during development and in experimental conditions in which the GABA system is altered. The brain region of major interest in these studies is the hippocampus.

The goals of a second but related group of studies are to identify the morphological and neurochemical changes that occur in epilepsy. Such changes are being studied in human tissue and in animal models of seizures. These models allow us to identify the changes that occur following an initial insult to the nervous system and then to determine the progression of morphological and neurochemical changes that may lead to the development of increased excitability and spontaneous seizures.

Publications

A selected list of publications:

Zhang N, Wei W, Mody I, Houser CR.   Altered localization of GABA(A) receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy, J Neurosci, 2007; 27(28): 7520-31.
Houser CR.   Interneurons of the dentate gyrus: An overview of cell types, terminal fields and neurochemical identity, Prog Brain Res, 2007; 163: 217-811.
Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I.   A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol, Nat Neurosci, 2007; 10(1): 40-8.
Chandra D, Jia F, Liang J, Peng Z, Suryanarayanan A, Werner DF, Spigelman I, Houser CR, Olsen RW, Harrison NL, Homanics GE.   GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol, Proc Natl Acad Sci U S A, 2006; 103(41): 15230-5.
Swartz BE, Houser CR, Tomiyasu U, Walsh GO, DeSalles A, Rich JR, Delgado-Escueta A.   Hippocampal cell loss in posttraumatic human epilepsy, Epilepsia, 2006; 47(8): 1373-82.
Liang J, Zhang N, Cagetti E, Houser CR, Olsen RW, Spigelman I.   Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors, J Neurosci, 2006; 26(6): 1749-58.
Peng Z, Houser CR.   Temporal patterns of fos expression in the dentate gyrus after spontaneous seizures in a mouse model of temporal lobe epilepsy, J Neurosci, 2005; 25(31): 7210-20.
Farrar C, Houser CR, Clarke S.   Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice, Aging Cell, 2005; 4(1): 1-12.
Farrar CE, Huang CS, Clarke SG, Houser CR.   Increased cell proliferation and granule cell number in the dentate gyrus of protein repair-deficient mice, J Comp Neurol, 2005; 493(4): 527-37.
Peng Z, Huang CS, Stell BM, Mody I, Houser CR.   Altered expression of the delta subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy, J Neurosci, 2004; 24(39): 8629-39.
Houser CR, Esclapez M.   Downregulation of the alpha5 subunit of the GABA(A) receptor in the pilocarpine model of temporal lobe epilepsy, Hippocampus, 2003; 13(5): 633-45.
Wei W, Zhang N, Peng Z, Houser CR, Mody I.   Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus, J Neurosci, 2003; 23(33): 10650-61.
Peng Z, Hauer B, Mihalek RM, Homanics GE, Sieghart W, Olsen RW, Houser CR.   GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain, J Comp Neurol, 2002; 446(2): 179-97.
Houser CR, Esclapez M, Zhang N.   GABA neurons of the hippocampal formation: Localization, vulnerability and plasticity, GABA in the Nervous System: The View at Fifty Years, 2000; 337-56.
Esclapez M, Houser CR.   Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy, J Comp Neurol, 1999; 412(3): 488-505.
Zhang N, Houser CR.   Ultrastructural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: a study of reorganized mossy fiber synapses, J Comp Neurol, 1999; 405(4): 472-90.
Houser CR.   Neuronal loss and synaptic reorganization in temporal lobe epilepsy, Adv Neurol, 1999; 79: 743-61.
Dupuy-Davies S, Houser CR.   Evidence for changing positions of GABA neurons in the developing rat dentate gyrus Hippocampus, 1999; 9(2): 186-99.
Houser, CR, Dupuy, ST, Zhang N.   Prominent expression of glutamate decarboxylase during early hippocampal development, Childhood Epilepsies and Brain Development, 1999; pp.13-24.
Dupuy ST, Houser CR.   Developmental changes in GABA neurons of the rat dentate gyrus: an in situ hybridization and birthdating study J Comp Neurol, 1997; 389(3): 402-18.
Dupuy ST, Houser CR.   Prominent expression of two forms of glutamate decarboxylase in the embryonic and early postnatal rat hippocampal formation J Neurosci, 1996; 16(21): 6919-32.
Esclapez, M, Chang D, Houser CR.   Subpopulations of GABA neurons in the dentate gyrus express high levels of the alpha1 subunit of the GABA-A receptor, Hippocampus, 1996; 6: 225-238.
Houser CR, Esclapez, M.   Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures Epilepsy Res, 1996; 26(1): 207-18.
Esclapez M, Houser CR.   Somatostatin neurons are a subpopulation of GABA neurons in the rat dentate gyrus: Evidence from co-localization of pre-prosomatostatin and glutamate decarboxylase mRNAs, Neuroscience, 1995; 64: 339-355.
Esclapez M, Tillakaratne NJ, Kaufman DL, Tobin AJ, Houser CR.   Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms J Neurosci, 1994; 14(3 Pt 2): 1834-55.
Houser CR, Esclapez M.   Localization of mRNAs encoding two forms of glutamic acid decarboxylase in the rat hippocampal formation Hippocampus, 1994; 4(5): 530-45.
Esclapez M, Tillakaratne NJ, Tobin AJ, Houser CR.   Comparative localization of mRNAs encoding two forms of glutamic acid decarboxylase with nonradioactive in situ hybridization methods J Comp Neurol, 1993; 331(3): 339-62.
Obenaus A, Esclapez M, Houser CR.   Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures J Neurosci, 1993; 13(10): 4470-85.
Houser CR   GABA neurons in seizure disorders: A review of immunocytochemical studies, Neurochem Res, 1991; 16: 295-308.
Kafman DL, Houser CR, Tocin AJ   Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions, J Neurochem, 1991; 56: 720-723.
Houser, CR   Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy, Brain Res, 1990; 535: 195-204.
Houser CR, Miyashiro JE, Swartz BE, Walsh GO, Rich JR, Delgado-Escueta AV.   Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy J Neurosci, 1990; 10(1): 267-82.
Houser Carolyn R, Zhang Nianhui, Peng Zechun, Huang Christine S, Cetina Yliana   Neuroanatomical clues to altered neuronal activity in epilepsy: from ultrastructure to signaling pathways of dentate granule cells Epilepsia, 2012; 53 Suppl 1(50): 67-77.
Soussi Rabia, Zhang Nianhui, Tahtakran Siroun, Houser Carolyn R, Esclapez Monique   Heterogeneity of the supramammillary-hippocampal pathways: evidence for a unique GABAergic neurotransmitter phenotype and regional differences The European journal of neuroscience, 2010; 32(5): 771-85.
Peng Zechun, Zhang Nianhui, Wei Weizheng, Huang Christine S, Cetina Yliana, Otis Thomas S, Houser Carolyn R   A reorganized GABAergic circuit in a model of epilepsy: evidence from optogenetic labeling and stimulation of somatostatin interneurons The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013; 33(36): 14392-405.
Li Yi, Peng Zechun, Xiao Bo, Houser Carolyn R   Activation of ERK by spontaneous seizures in neural progenitors of the dentate gyrus in a mouse model of epilepsy Experimental neurology, 2010; 224(1): 133-45.
Mathews Paul J, Lee Ka Hung, Peng Zechun, Houser Carolyn R, Otis Thomas S   Effects of climbing fiber driven inhibition on Purkinje neuron spiking The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012; 32(50): 17988-97.
Wyeth Megan S, Zhang Nianhui, Mody Istvan, Houser Carolyn R   Selective reduction of cholecystokinin-positive basket cell innervation in a model of temporal lobe epilepsy The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010; 30(26): 8993-9006.
Houser Carolyn R, Zhang Nianhui, Peng Zechun, Huang Christine S, Cetina Yliana   Neuroanatomical clues to altered neuronal activity in epilepsy: from ultrastructure to signaling pathways of dentate granule cells Epilepsia, 2012; 53 Suppl 1(50): 67-77.