Bradley E. Alger, PhD

Soltesz I, Alger BE, Kano M, Lee SH, Lovinger DM, Ohno-Shosaku T, Watanabe M (2015)  Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy. Nature Reviews in Neuroscience. 16:264-77. doi: 10.1038/nrn3937.

Mattison HA, Bagal AA, Mohammadi M, Pulimood NS, Reich CG, Alger BE, Kao JP, Thompson SM. (2014). Evidence of calcium-permeable AMPA receptors in dendritic spines of CA1 pyramidal neurons. Journal of Neurophysiology.  Apr 23. [Epub ahead of print] PMCID: PMC4064414

Nagode DA, Tang AH, Yang K, Alger BE. (2014) Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1.  Journal of Physiology. 592:103-23. doi: 10.1113/jphysiol.2013.257428. Epub 2013 Nov 4.  PMCID: PMC3903354

Dean SL, Wright CL, Hoffman JF, Wang M, Alger BE, McCarthy MM. (2012) Prostaglandin E2 stimulates estradiol synthesis in the cerebellum postnatally with associated effects on Purkinje neuron dendritic arbor and electrophysiological properties. Endocrinology. 153:5415-27. PMCID: PMC3473195

Kim J, Alger BE (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid signaling in hippocampus. Nature Neuroscience. 7:697-699.

Alger BE (2013) Getting high on the endocannabinoid system. Cerebrum 2013:14. eCollection. PMCID: PMC3997295

Santos MD, Mohammadi MH, Yang S, Liang CW, Kao JP, Alger BE, Thompson SM, Tang CM. (2012) Dendritic hold and read: a gated mechanism for short term information storage and retrieval. PLoS One. 7(5):e37542. PMCID: PMC3358290

Kim J, Tsien RW, Alger BE (2012) An improved test for detecting multiplicative homeostatic synaptic scaling. PLoS One. 7(5):e37364. PMCID: PMC3355135

Alger BE, Tang AH. (2012) Do cannabinoids reduce brain power?  Nat Neurosci. Mar 27;15(4):499-501.  PMCID: PMC3388600

Wang M, Hill MH, Zhang L, Gorzalka B, Hillard CJ, Alger BE (2012) Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. Journal of Psychopharmacologu. (Sep 2011, ePUB on-line) 26:56-71. PMCID: PMC3373303

Nagode, DA, Tang AH, Karson, MA, Klugmann, M, Alger BE (2011) Optogenetic release of ACh induces rhythmic bursts of perisomatic IPSCs in hippocampus. PLoS ONE 6:e27691.  PMCID: PMC3218010

Tang AH, Karson MA, Nagode DA, McIntosh JM, Uebele VN, Renger JJ, Klugmann M, Milner TA, Alger BE (2011) Nerve terminal nAChRs initiate quantal GABA release from perisomatic interneurons by activating axonal T-type (Cav3) Ca2+ channels and Ca2+ release from stores. Journal of Neuroscience. 31:13546-13561. PMCID: PMC3353409

Waddell J, Kim J, Alger BE, McCarthy MM (2011) The Depolarizing Action of GABA in Cultured Hippocampal Neurons Is Not Due to the Absence of Ketone Bodies. PLoS One 6(8):e23020. PMCID: PMC3158756

Zhang L, Wang M, Bisogno T, Di Marzo V, Alger BE (2011) Endocannabinoids generated by Ca2+ or by metabotropic glutamate receptors appear to arise from different pools of diacylglycerol lipase. PLoS One Jan 28; 6(1):e16305. PMCID: PMC3030617

Zhang L, Alger BE (2010) Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome. Journal of Neuroscience 30:5724-5729.  PMCID: PMC2906112

Kim J, Alger BE (2010) Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses. Nature Neuroscience 13:592-600.  PMCID: PMC2860695

Karson MA, Tang AH, Milner TA, Alger BE (2009) Synaptic cross talk between perisomatic-targeting interneuron classes expressing cholecystokinin and parvalbumin in hippocampus. Journal of Neuroscence. 29:4140-54.  PMCID: PMC2853357

Lafourcade CA, Alger BE (2008) Distinctions among GABAA and GABAB responses revealed by calcium channel antagonists, cannabinoids, opioids and synaptic plasticity in rat hippocampus. Psychopharmacology. (Dec 2007; ePUB on-line) 198:539-549.  PMCID: PMC2906116

Edwards DA, Zhang L, Alger BE (2008) Metaplastic control of hippocampal endocannabinoid responses. Proceedings of the National Academy of Sciences (USA), 105:8142-8147.  PMCID: PMC2409138

Reich CG, Mohammadi M, Alger BE (2008) Endocannabinoid modulation of responses in multiple-trial trace and delay fear conditioning. J Psychopharmacol (Feb 2008; ePUB on-line) 22:769-77.  PMCID: PMC2906780

Karson MA, Whittington KC, Alger BE (2008) Cholecystokinin inhibits endocannabinoid-sensitive hippocampal IPSPs and stimulates others. Neuropharmacol (July 2007; ePUB on-line) 54:117-128.  PMCID: PMC2242378

Edwards DA., Kim J, Alger BE (2006) Multiple mechanisms of endocannabinoid response initiation in hippocampus. Journal of Neurophysiology. (ePUB online October 5, 2005) 95:67-75.

Isokawa M, Alger BE (2006) The ryanodine receptor regulates endogenous cannabinoid mobilization in the hippocampus. Journal of Neuropysiology. (ePUB online February 5, 2006) 95:3001-3011.

Reich CG, Karson MA, Karnup SV, Jones LM, Alger BE (2005) Regulation of IPSP theta rhythm by muscarinic receptors and endocannabinoids in hippocampus. Journal of Neurophysiology. 94:4290-4299.

Isokawa M, Alger BE (2005) Retrograde endocannabinoid regulation of GABAergic inhibition in the rat dentate gyrus granule cell. Journal of Physiology. 567:1001-1010.

Heinbockel T, Brager DH, Reich CG, Zhao J, Muralidharan S, Alger BE, Kao, J.P. (2005) Endocannabinoid signaling dynamics probed with optical tools.  Journal of Neuroscience. 25:9449-9459.

Brager DH, Luther PW, Edrélyi F, Szabó G, Alger BE (2003) Regulation of exocytosis from single visualized GABAergic boutons in hippocampal slices. Journal of Neuroscience. 23:10475-10486.

Reich CG, Mason SE, Alger BE (2003) A novel form of LTD induced by transient, partial inhibition of the Na,K-pump in rat hippocampal CA1 cells. Journal of Neurophysiology. 91:239-247.

Vaillend C, Mason SE, Cuttle MF, Alger BE (2002) Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+, K+ -ATPases in the rat CA1 hippocampal region. Journal of Neurophysiology. 88:2963-2978

Carlson G, Wang Y, Alger BE (2002) Endocannabinoids facilitate the induction of LTP in the hippocampus. Nature Neuroscience. 5(8):723-4.

Kim J., Isokawa M, Ledent C, Alger BE (2002) Activation of muscarinic acetylcholine receptors enhances the release of endocannabinoids in the hippocampus. Journal of Neuroscience. 22: 10182-91

Varma N, Brager DH, Morishita W, Lenz RA, London B, Alger BE (2002) Presynaptic factors in the regulation of DSI expression in hippocampus. Neuropharmacology. 43: 550-562.

Carlson G, Wang Y, Alger BE (2002) Endocannabinoids facilitate the induction of LTP in the hippocampus. Nature Neuroscience. 5: 723-724.

Kim J, Alger BE (2002) Random response fluctuations lead to spurious paired-pulse facilitation.  Journal of Neuroscience. 21:9608-18.

My colleagues and I studied 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 modeled in an in vitro brain slice preparation, and their occurrence depends on the state of neuronal excitability in the tissue. We used 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 tried 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?

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.

The laboratory is now closed.