Endogenous Cannabinoids:
The activity of cortical pyramidal cells, the sole output cells of the cortex, is tightly controlled by distinct classes of GABAergic inhibitory interneurons. These interneurons maintain high firing rates in vivo and provide potent inhibition to pyramidal cells, thus regulation of this inhibitory tone is essential for proper cortical function. Recent data from our laboratory and others indicate that the cannabinoid system may play an important role in modulating GABAergic inhibition. The type 1 cannabinoid (CB1) receptor, found in presynaptic terminals of GABAergic neurons, is one of the most highly expressed G-protein coupled receptors in the forebrain, and mediates the well-known effects of exogenous cannabinoids on cognition, mood, and behavior.

Endogenous cannabinoid-like compounds are released from pyramidal neurons with a high degree of spatial and temporal specificity and travel backwards across the synapse to regulate GABA release from presynaptic terminals. Little is known, however, about the physiological role of this endogenous system. Our current strategy combines electrophysiological, biochemical, pharmacological, and optical imaging techniques to: 1) determine the neuronal activity patterns that induce the release of endogenous cannabinoids, 2) identify the specific inhibitory inputs to pyramidal cells that are modulated by cannabinoids, and 3) investigate the consequences of cannabinoid signaling on synaptic integration in cortical circuits.

 

Nerve Growth Factors:
NGF and related members of the neurotrophin gene family play critical roles in nervous system development by promoting cell survival and differentiation. These factors have also been implicated in the pathophysiologic mechanisms underlying Alzheimer's and other neurodegenerative diseases. Recently it has been shown that neurotrophins have potent effects as synaptic modulators as well. In particular, we have found that BDNF (brain-derived neurotrophic factor) regulates synaptic transmission and plasticity by modulating the activity of both NMDA receptors and GABA receptors in the hippocampus. We are exploring this phenomenon at the biochemical, single channel, and synaptic circuit level. Ongoing projects aim to characterize the underlying molecular signaling cascades and define the functional roles of neurotrophin-induced plasticity within the hippocampus and neocortex.

Recent Publications

Madara, J.C., and Levine, E.S. Simultaneous presynaptic and postsynaptic effects of BDNF are mediated by NMDA Receptors. submitted..

Fortin D.A. and Levine E. S. (2006) Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons. Cerebral Cortex. Feb 8; [Epub ahead of print].

Fogal, B., Trettel, J., Uliasz, T. F., Levine, E. S., and Hewett, S. J. (2005) Changes in secondary glutamate release underlie the developmental regulation of excitotoxic neuronal cell death, Neuroscience, 132: 929-942.

Kolb, J. E., Trettel, J. and Levine, E. S. (2005) BDNF enhancement of postsynaptic NMDA receptors is blocked by ethanol. Synapse, 55: 52-57.

Fortin, D. A., Trettel, J. and Levine, E. S. (2004) Brief trains of action potentials enhance pyramidal neuron excitability via endocannabinoid-mediated suppression of inhibition. J Neurophysiology, 92:2105-2112.

Trettel J. Fortin D. A. and Levine E. S. (2004) Endocannabinoid signalling selectively targets perisomatic inhibitory inputs to pyramidal neurones in juvenile mouse neocortex. J. Physiology, 556: 95-107.

Trettel, J. and Levine, E. S. (2003) Endocannabinoids mediate rapid retrograde signaling at
interneuron - pyramidal neuron synapses of the neocortex. J. Neurophysiology, 89: 2334-2338.

Trettel, J. and Levine, E. S. (2002) Cannabinoids depress inhibitory synaptic inputs received by layer 2/3 pyramidal neurons of the neocortex. J. Neurophysiology, 88: 534-539.

Levine, E. S. (2001) Neurotrophins and Hippocampal Plasticity, in Neurobiology of the Neurotrophins, I. Mocchetti (ed.), F. P. Graham Publishing, pp. 165-186.

Kolb, J. E. and Levine, E. S. (2000) Brain-derived neurotrophic factor increases activity of NR2B-containing NMDA receptors in excised patches from hippocampal neurons, J Neurosci Res, 62: 357-362.

Levine, E. S. and Black, I. B. (2000) Trophic Interactions and Neuronal Plasticity, in The New Cognitive Neurosciences, M. S. Gazzaniga (ed.), MIT Press, pp. 159-170.

Levine, E. S. and Black, I. B. (2000) Neurotrophic Factors, in Comprehensive Textbook of Psychiatry, B. J. Sadock and V. A. Sadock (eds.), Lippincott Williams & Wilkins, pp. 71-76.