Faculty Profile:

Bradley E. Alger, Ph.D.
Professor

Departments of Physiology and Psychiatry
School of Medicine

410-706-3350

balgerlab@gmail.com

Research

My colleagues and I study the neurophysiological basis of epilepsy and of learning and memory in the mammalian brain. These disparate phenomena have common features: They have prominent electrophysiological manifestations in the hippocampus, they can be modelled in an in vitro brain slice preparation, and their occurrence depends on the state of neuronal excitability in the tissue. We use state-of-the-art electrophysiological techniques (intracellular, whole-cell, patch-clamp, field potential) in the hippocampal slice to investigate an aspect of excitability control that is crucial for the establishment of memory traces and for the prevention of epileptic seizures: the strength of synaptic inhibition mediated by the neurotransmitter, GABA.

Decreases in GABA inhibition facilitate the induction of long-term potentiation (LTP), an increase in synaptic excitation that is the primary candidate for the neurophysiological basis of learning and memory. Decreases in GABA inhibition also promote the onset of the epileptic seizure, a state of hyperexcitability characteristic of epilepsy. How does the nervous system maintain the fine distinction necessary to encourage the former while preventing the latter? What cellular controls on inhibition are normally present in the brain and how are these controls altered in physiological and pathophysiological ways? These are the sorts of questions we try to answer.

We discovered a new mode of cellular communication that may solve part of the puzzle: the target (pyramidal) cells, the ones towards which inhibition is directed, may regulate their own state of inhibition by sending a signal backwards across the synaptic junctions (retrograde signaling) and thereby causing the inhibitory interneurons to stop releasing GABA temporarily. Many laboratories have begun studying this phenomenon, and the most interesting and surprising thing is that the signal from the pyramidal cell to the interneuron is a molecule that has been called "the brain's own marijuana". In the mammalian brain are specialized receptors that recognize and bind to the active ingredient in marijuana, THC. The natural compound that is active at these receptors is not THC, of course, but an "endocannabinoid," a molecule recently recognized as capable of carrying signals between brain cells. How do these molecules normally work? What can they teach us about the mechanisms of drug abuse and potential medical use of marijuana and other cannabinoids? We will use a variety of experimental approaches to resolve these interesting problems.

Lab Techniques

Preparations: acute in vitro hippocampal slices; tissue cultured hippocampal slices and cells.
Electrophysiological techniques: intracellular and extracellular recordings; whole-cell voltage-and current clamp; intradendritic, single channel and perforated patch recordings.
Imaging techniques: intracellular calcium-imaging, and confocal and two-photon microscopy to study labeled cells in slices; infra-red, differential interference contrast visualization of cells in living slices.

Publications

Since 2000

63. Morishita, W. and Alger, B. E. (2000) Differential effects of the group II mGluR agonist, DCG-IV, on depolarization-induced suppression of inhibition in hippocampus. Hippocampus 10:261-268.

64. Morishita, W. and Alger, B. E. (2001) Direct depolarization and antidromic action potentials transiently suppress dendritic IPSPs in hippocampal CA1 pyramidal cells. J. Neurophysiol. 85:480-484.

65. Martin, L. A., Wei, D.-S. and Alger, B. E. (2001) Heterogeneous susceptibility of GABAA receptor-mediated IPSCs to depolarization-induced suppression of inhibition in rat hippocampus. J. Physiol. 532:685-700.

66. Ursitti, J. A., Martin, L., Resneck, W. G., Chaney, T., Zielke, C., Alger, B. E. and Bloch, R. J. (2001) Spectrins in developing rat hippocampal cells. Dev. Brain Res. 129:81-93.

67. Kim, J. and Alger, B. E. (2001) Random response fluctuations lead to spurious paired-pulse facilitation. J. Neurosci. 21:9608-9618.

68. Varma, N., Carlson, G. C., Ledent, C. and Alger, B. E. (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21:RC188 (1-5).

69. Carlson, G., Wang, Y. and Alger, B. E. (2002) Endocannabinoids facilitate the induction of LTP in the hippocampus. Nature Neurosci. 5:723-724.

70. Varma, N., Brager, D. H., Morishita, W., Lenz, R. A., London, B. and Alger, B. E. (2002) Presynaptic factors in the regulation of DSI expression in hippocampus. Neuropharmacology. 43:550-562.

71. Kim, J., Isokawa, M., Ledent, C. and Alger, B. E. (2002) Activation of muscarinic acetylcholine receptors enhances the release of endocannabinoids in the hippocampus. J. Neurosci. 22:10182-10191.

72. Alger, B. E. (2002) Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68:247-286.

73. Vaillend, C., Mason, S. E., Cuttle, M. F. and Alger, B. E. (2002) Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+, K+-ATPases in the rat CA1 hippocampal region. J. Neurophysiol. 88:2963-2978.

74. Brager, D.H., Luther, P.W., Edrélyi, F., Szabó, G. and Alger, B. E. (2003) Regulation of exocytosis from single visualized GABAergic boutons in hippocampal slices. J. Neurosci. 23:10475-10486.

75. Reich, C.G., Mason, S.E. and Alger, B. E. (2003) A novel form of LTD induced by transient, partial inhibition of the Na,K-pump in rat hippocampal CA1 cells. J. Neurophysiol. 91:239-247.

76. Kim, J. and Alger, B.E. (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nature Neurosci. 7:697-698.

77. Reich, C.G., Karson, M.A., Karnup, S.V., Jones, L.M. and Alger, B.E. (2005) Regulation of IPSP theta rhythm by muscarinic receptors and endocannabinoids in hippocampus. J. Neurophysiol. 94:4290-4299.

78. Isokawa, M. and Alger, B.E. (2005) Retrograde endocannabinoid regulation of GABAergic inhibition iin the rat dentate gyrus granule cell. J. Physiol. 567:1001-1010.

79. Heinbockel, T., Brager, D.H., Reich, C.G., Zhao, J., Muralidharan, S., Alger, B.E. and Kao, J.P. (2005) Endocannabinoid signaling dynamics probed with optical tools.

J. Neurosci. 25: 9449-9459.

80. Edwards, D.A., Kim, J. and Alger, B.E. (2006) Multiple mechanisms of endocannabinoid response initiation in hippocampus. J. Neurophysiol. 95:67-75.

81. Isokawa, M. and Alger, B.E. (2006) The ryanodine receptor regulates endogenous cannabinoid mobilization in the hippocampus. J. Neurophysiol. (epub on-line, Feb. 2006), 95:3001-3011.

82. Karson, M.A., Whittington, K.C. and Alger, B.E. (2008) Cholecystokinin inhibits
endocannabinoid-sensitive hippocampal IPSPs and stimulates others. Neuropharmacol.
(epub on-line, July 2007) 54:117-128.

83. Reich C.G., Mohammadi M., and Alger, B.E. (2008) Endocannabinoid modulation of fear responses: learning and state-dependent performance effects. J. Psychopharmacol., (epub on line, Feb. 2008) 22:769-777.

84. Edwards, D.A, Zhang, L., and Alger, B.E. (2008) Metaplastic control of hippocampal
endocannabinoid responses. Proc Natl Acad Sci USA, 105:8142-8147

85. Lafourcade, C.A. and Alger, B.E. (2008) Distinctions among GABAA and GABAB responses revealed by calcium channel antagonists, cannabinoids, opioids and synaptic plasticity in rat hippocampus. Psychopharmacol., (epub on-line, Dec. 2007), 198:539-549.

86. Karson, M.A.,Tang, A-H, Milner, T.A., and Alger, B.E. (2009) Synaptic cross talk between perisomatic interneuron classes expressing cholecystokinin and parvalbumin in hippocampus. J. Neurosci., 29:4140-4154.

88. Lafourcade, C.A., Zhang, L., and Alger, B.E. (2009) Novel mGluR- and CB1R-independent suppression of GABA release caused by a contaminant of the group I metabotropic glutamate receptor agonist, DHPG. PLoS ONE 4(7):e6122.

Personal History

I got my B.A. at the University of California, Berkeley in 1972, and Ph.D. from Harvard University in 1977. My Ph.D. thesis was done in the rat hippocampal slice and included some of the early studies on LTP. I did my postdoctoral training with Roger Nicoll at UCSF from 1977 to 1981. In 1981 I became an Assistant Professor in Department of Physiology at the UMB School of Medicine and in 1992 was promoted to Professor with tenure. Work in my lab is supported by NIH funding.

Laboratory Personnel

Research Associate

Jimok Kim, Ph.D.

Postdoctoral Fellows

Miranda A. Karson, Ph.D.

Longhua Zhang, Ph.D.

Meina Waing, Ph.D.

Ai-hui Tang, Ph.D.

Graduate Students

Kevin C. Whittington

Daniel A. Nagode

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