Department Affiliation: Primary: Neuroscience; Secondary: Biological Chemistry; Howard Hughes Medical Institute
Degree: Ph.D., Cornell University
Rank: Professor/Director, Department of Neuroscience
Telephone Number: 410-955-4050
Fax Number: 410-955-0877
E-mail address: firstname.lastname@example.org
Homepage: Huganir Lab Homepage
School of Medicine Address: 1009A Hunterian Bldg., 725 N. Wolfe St., Baltimore, MD 21205
Regulation of Neurotransmitter Receptors and Brain Function in Heath and Disease
Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of synaptic connections between neurons in the nervous system. We have been studying the molecular mechanisms in the regulation of neurotransmitter receptor function. Recently we have focused on glutamate receptors, the major excitatory receptors in the brain. Glutamate receptors can be divided into two major classes: AMPA and NMDA receptors. AMPA receptors mediate rapid excitatory synaptic transmission while NMDA receptors play important roles in neuronal plasticity and development. Studies in our laboratory have found that both AMPA and NMDA receptors are multiply phosphorylated by a variety of protein kinases. Phosphorylation regulates several functional properties of these receptors including conductance and membrane targeting. Recent studies in our lab have demonstrated that the phosphorylation of AMPA receptors is regulated during cellular models of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). Moreover, phosphorylation of the AMPA receptor GluR1 subunit is required for the expression of these forms of plasticity and for the retention of spatial memory and also regulates emotional memory formation and erasure.
We have also been examining the mechanisms of the subcellular targeting and clustering of glutamate receptors at synapses. We have recently identified a variety of proteins that directly or indirectly interact with AMPA and NMDA receptors. We have found a novel family of proteins that we call GRIPs (Glutamate Receptor Interacting Proteins) that directly bind to the C-termini of the GluR2/3 subunits of AMPA receptors. GRIPs contain seven PDZ domains, protein-protein interaction motifs, which crosslink AMPA receptors to each other or link them to other proteins. In addition, we have found that the C-termini of GluR2 also interacts with the PDZ domain of PICK1, a protein kinase C-binding protein that is found at excitatory synapses. The GluR2 subunit also interacts with the NSF protein, a protein involved in the regulation of membrane fusion events. These AMPA receptor interacting proteins are critical in the proper membrane trafficking and synaptic targeting of these receptors. We have shown that the binding of PICK1 and GRIP is required for a specific form of LTD in the cerebellum that is a cellular model for motor learning. Moreover, we have found that this receptor complex is critical for hippocampal LTP and LTD and spatial learning.
In addition to these studies on AMPA receptors, we have been characterizing a separate NMDA receptor associated protein complex that is important in synaptic targeting and downstream signaling of NMDA receptors. We have identified an excitatory synapse specific rasGAP, which we call synGAP that regulates synaptic Ras signaling and has profound effects on synaptic plasticity.
Importantly, recent evidence has implicated glutamate receptor associated complexes in several neurological and psychiatric disorders including Alzheimer’s disease, schizophrenia, autism, mental retardation as well as in chronic pain and drug addiction.
In summary, we have examined the molecular mechanisms underlying the regulation of neurotransmitter receptor function. Our studies have suggested that regulation of receptor function may be a major mechanism for the regulation of synaptic plasticity in the nervous system in health and disease and may be an important determinant of animal behavior.
- Volk, L.J., Bachman, J.L., Johnson, R., Yu, Y., Huganir, R.L. (2013) PKM-Z is not required for hippocampal synaptic plasticity, learning and memory. Nature 493(7432): 420-3. Pub Med Reference
- Thomas, G.M., Hayashi, T., Chiu, S.L., Chen, C.M., Huganir, R.L. (2012) Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron 73(3):482-96. Pub Med Reference
- Makuch, L., Volk, L., Anggono, V., Johnson, R.C., Yu, Y., Duning, K., Kremerskothen, J., Xia, J., Takamiya, K., Huganir, R.L. (2011) Regulation of AMPA receptor function by the human memory-associated gene KIBRA. Neuron 71(6):1022-9. Pub Med Reference
- Makino, Y., Johnson, R.C., Yu, Y., Takamiya, K., Huganir, R.L. (2011) Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. Proc Natl Acad Sci USA. 108(20):8450-5. Epub 2011 May 2. Pub Med Reference
- Mejias, R., Adamczyk, A., Anggono, V., Niranjan, T., Thomas, G.M., Sharma, K., Skinner, C., Schwartz, C.E., Stevenson, R.E., Fallin, M.D., Kaufmann, W., Pletnikov, M., Valle, D., Huganir, R.L., Wang, T. (2011) Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism. Proc Natl Acad Sci USA. 108(12):4920-5. Pub Med Reference
- Clem, R. and Huganir, R.L. (2010) Calcium-permeable AMPA receptor dynamics mediate fear memory erasure, Science 330(6007): 1108-12. Pub Med Reference
- Hayashi, T., Thomas, G., Huganir, R.L. (2009) Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking. Neuron 64(2): 213-226. Pub Med Reference
- Lin, D.T., Makino, Y., Sharma, K., Hayashi, T., Neve, R., Takamiya, K., Huganir, R.L. (2009) Regulation of AMPA receptor GluR1 subunit extrasynaptic insertion events by 4.1N, phosphorylation and palmitoylation. Nat. Neurosci. 12(7): 879-87.� PMCID:� PMC2712131. Pub Med Reference
- Sia, G.-M., Beique, J.-C., Rumbaugh, G., Cho, R., Worley, P.F., Huganir, R.L. (2007) Interaction of the N-terminal domain of the AMPA Receptor GluR4 subunit with the Neuronal Pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55(1): 87-102. Pub Med Reference
- Steinberg, J.P., Takamiya, K., Shen, Y., Xia, J., Rubio, M.E., Yu, S., Jin, W., Thomas, G.M., Linden, D.J., Huganir, R.L. (2006) Targeted In Vivo Mutations of the AMPA Receptor Subunit GluR2 and its Interacting Protein PICK1 Eliminate Cerebellar Long-Term Depression. Neuron. 49(6): 845-60. Pub Med Reference
- Chung, H.J., Steinberg, J.P., Huganir, R.L. and Linden, D.J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751-1755, 2003. Pub Med Reference
- Lee, H-K., Takamiya, K., Han, J-S., Man, H., Kim, C.-H., Rumbaugh, G., Yu, S., Ding, L., He, C., Petralia, R.S., Wenthold, R.J., Gallagher, M., and Huganir, R.L. (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:631-643. Pub Med Reference
- Lee, H.K., Barbarosie, M., Kameyama, K., Bear, M.F., and Huganir, R.L. (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405:955-959. Pub Med Reference
- Ehlers, M.D., Zhang, S., Bernhardt, J.P., and Huganir R.L. (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with NR1 subunit. Cell 84:745-755. Chung, H.J., Steinberg, J.P., Huganir, R.L. and Linden, D.J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751-1755, 2003. Pub Med Reference
Other graduate programs in which Dr. Huganir participates: