Dr. Huganir’s research focuses on the molecular mechanisms that modulate the communication between neurons in the brain. This modulation is critical for complex processes in the brain, including learning, memory, and development. Disruption of these processes is also involved in several neurological and psychiatric diseases.
The Huganir laboratory studies the mechanisms that regulate synaptic transmission and synaptic plasticity. The general approach they have taken is to focus on molecular and cellular mechanisms that regulate neurotransmitter receptors. These receptors mediate the response of neurons to neurotransmitters released at synapses and are a central convergence point for transmission of signals between neurons. Modulation of the function of these receptors is a powerful and efficient way to modulate synaptic communication and synaptic plasticity. Over the years they have shown that receptor protein phosphorylation and the regulation of the synaptic targeting of receptors are dynamically regulated and regulate the efficiency of synaptic transmission. They are currently focusing their efforts on the mechanisms that underlie the regulation of the glutamate receptors, the major excitatory neurotransmitter receptors in the brain. These receptors are neurotransmitter-dependent ion channels that allow ions to pass through the neuronal cell membrane, resulting in the excitation of neuronal activity.
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.
Lab Website: Laboratory of Richard L. Huganir
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Miller EC, Teravskis PJ, Dummer BW, Zhao X, Huganir RL, Liao D. "Tau phosphorylation and tau mislocalization mediate soluble Aβ oligomer-induced AMPA glutamate receptor signaling deficits." Eur J Neurosci. 2014 Apr;39(7):1214-24. doi: 10.1111/ejn.12507.
Hayashi-Takagi A, Araki Y, Nakamura M, Vollrath B, Duron SG, Yan Z, Kasai H, Huganir RL, Campbell DA, Sawa A. "PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence." Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6461-6. doi:
Rathje M, Fang H, Bachman JL, Gether U, Huganir RL, Madsen KL. "Reply to Wilkinson et al.: Concerning the use of pHluorin-tagged GluA2 as a reporter for NMDA-induced AMPA receptor recycling." Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):E305. No abstract available.
Jenkins MA, Wells G, Bachman J, Snyder JP, Jenkins A, Huganir RL, Oswald RE, Traynelis SF. "Regulation of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function by protein kinase C at serine-818 and threonine-840." Mol Pharmacol. 2014 Apr;85(4):618-29. doi: 10.1124/mol.113.091488. Epub 2014 Jan 22.
Sharma K, Choi SY, Zhang Y, Nieland TJ, Long S, Li M, Huganir RL. "High-throughput genetic screen for synaptogenic factors: identification of LRP6 as critical for excitatory synapse development." Cell Rep. 2013 Dec 12;5(5):1330-41. doi: 10.1016/j.celrep.2013.11.008.