Ph.D., Yale, 1986

My major research focus for many years has been on synaptic plasticity, the strengthening or weakening of synaptic connections between neurons. Synaptic plasticity is a basic property of excitatory synapses in the central nervous system and is used in distinct brain regions for neuroadapations to various environmental stimuli. My lab's work has been focused in two brain regions: the hippocampus where synaptic plasticity is required for new memory formation, and the midbrain ventral tegmental area (VTA), where we are exploring the hypothesis that synaptic plasticity is an early change that is essential for addiction to drugs of abuse. My lab uses electrophysiological recordings from neurons in acutely prepared brain slices. We have also utilized viral transfection, transgenic mice, and other tools to manipulate the protein environment in neurons to probe the role of particular molecules in synaptic function.

In the hippocampus, our work has been at two levels. One involves questions about the basic cell biology of how synapses regulate their strength. In this we have collaborated with Dr. Michael Ehlers at Duke University, a recently named Howard Hughes Investigator, who is an accomplished molecular biologist and who has provided tools for our investigation. In collaboration with Mike, we have demonstrated that the postsynaptic AMPA class of glutamate receptors that are inserted into the postsynaptic membrane during long-term synaptic potentiation (LTP) are derived from a specific compartment, the recycling endosome. In our ongoing collaboration with the Ehlers lab, we are now investigating the role of related synaptic proteins in the trafficking of the relevant AMPA receptors.

In a second set of studies, we have worked at the circuit level, comparing synaptic plasticity at hippocampal excitatory synapses on excitatory pyramidal cells and on inhibitory interneurons. The two behave entirely differently in response to the same afferent stimulation. In 1997 my lab discovered a form of long-term synaptic depression (LTD) at excitatory synapses onto interneurons. Our recent work demonstrates that this LTD depends upon a retrograde signal likely to be an endogenous cannabinoid-like molecule.

My lab has been one of the first to examine the relationship between synaptic plasticity and drugs of abuse. We and others have found that after even a single exposure to a drug of abuse in vivo, synapses in the VTA are potentiated. Amphetamine produces this potentiation within two hours of administration, consistent with an LTP-like mechanism. We have also demonstrated that a form of LTD at the same synapses is entirely blocked by brief exposure in vitro to low doses of amphetamine. We believe that the block of LTD by psychostimulant drugs may promote LTP of the same synapses and contribute to the development of addiction.

We currently have two major directions in the VTA. First, we have discovered an entirely novel form of plasticity at VTA synapses. Little has previously been known about plasticity of inhibitory GABAergic synapses, and indeed many inhibitory synapses do not exhibit plasticity like their excitatory neighbors. We now find that inhibitory GABAergic VTA synapses express robust LTP mediated by an entirely novel intracellular signaling cascade. This LTPGABA is entirely blocked by morphine, suggesting a novel site of action for this drug in the reward circuit. Our second VTA project is a collaboration with Dr. Marina Picciotto at Yale University. Dr. Picciotto has generated several interesting transgenic mice with alterations in specific subunits of the nicotinic acetylcholine receptor confined to specific neuronal populations in the VTA. We are interested in exploring the link between nicotine actions in the VTA and alterations in synaptic transmission.

Overall, our work in synaptic plasticity in both hippocampus and VTA demonstrates that multiple signaling pathways are utilized at various CNS synapses to bring about changes in synaptic strength. Furthermore, our work in the reward system underlines the idea that changes in synaptic strength contribute to neuroadaptations of many brain systems beyond those used to store memory per se. The interactions of drugs of abuse with LTP and LTD mechanisms illustrate this idea: distinct environmental inputs may modify or perturb existing brain systems to bring about long-lasting behavioral changes. My work thus is relevant both at the basic level, describing the building blocks of the nervous system, and at the translational level, suggesting targets for therapeutics that may enhance memory or combat addiction.

Cellular physiology and biophysics (BI0110)
Synaptic transmission and plasticity (BI0119)

• Kauer J.A. and Malenka R.C. (2007) Synaptic plasticity and addiction. Nature Reviews Neurosci., in press.
• Nugent, F.S., Penick, E.C., and Kauer, J.A. (2007) Opioids block long-term potentiation of GABAergic synapses. Nature 446:1086-1090.
• Kauer J.A. and Malenka R.C. (2006) LTP: AMPA receptors trading places. Nat Neurosci. 9: 593-4.
• Mair, R.C. and Kauer, J.A. (2006) Amphetamine depresses excitatory synaptic transmission at prefrontal cortical layer V synapses. Neuropharmacol. 52: 193-199.
• Kauer, J. A. (2004) Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Ann. Rev. Physiol. 66: 447-475.
• Park, M., Penick, E.C., Edwards J.G., Kauer, J.A. and Ehlers, M.D. (2004) Recycling endosomes supply AMPA receptors for LTP. Science 305: 1972-1975.
• Gutlerner, J.L., E.C. Penick, E. M. Snyder and J. A. Kauer (2002) Novel PKA-dependent long-term depression of excitatory synapses. Neuron 36: 921-931.
• Jones, S., Kornblum, J.L., and J.A. Kauer. (2000) Amphetamine blocks long-term depression of ventral tegmental area synapses. J. Neurosci. 20: 5575-5580.
• McMahon, L.L., and J. A. Kauer (1997) Hippocampal interneurons express a novel form of synaptic plasticity. Neuron 18: 1-11.