Excitatory synaptic transmission in the central nervous system is largely mediated by the AMPA and NMDA subtypes of ionotropic glutamate receptors (AMPAR and NMDAR, respectively). Because AMPARs mediate the bulk of glutamatergic synaptic transmission, excitatory efficacy is commonly associated with the magnitude of AMPAR-mediated synaptic responses. While postsynaptic NMDARs are well-known for gating several forms of activity-dependent plasticity (e.g. long-term potentiation and long-term depression) of AMPAR-mediated transmission, NMDARs can also contribute to information transfer at synapses and to neuronal excitability. In addition, certain synapses localize NMDARs to the presynaptic compartment where their activation by synaptically-released glutamate can regulate neurotransmitter release. Moreover, an expanding body of evidence indicates that NMDARs themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. However, many of the mechanisms underlying NMDAR plasticity are poorly understood. Thus far, most studies addressing NMDAR regulation have been performed in expression systems and cultured neurons. As a result, the extent to which similar mechanisms apply to the in vivo situation remains largely unknown. Furthermore, scant knowledge exists on the mechanisms of induction and expression of NMDAR plasticity. In this proposal, we will attempt to fill this knowledge gap by analyzing two key hippocampal synapses that express robust NMDAR plasticity. The overarching hypothesis is that common mechanisms underlie dynamic regulation of NMDARs across synapses. Using a combination of complementary experimental approaches, such as electrophysiology in acute hippocampal slices, optogenetics, immunoelectron microscopy, calcium imaging, in vivo knockdown strategies and transgenic mice, we will investigate the role of specific signaling pathways and receptor subunits in NMDAR plasticity. In addition, we will determine whether presynaptic NMDARs are regulators of short-term and long-term synaptic plasticity, and whether NMDAR plasticity is developmentally regulated. Dysregulation of NMDARs has been implicated in a wide range of neuropsychiatric disorders, such as schizophrenia, epilepsy, chronic pain, addiction to drugs, Alzheimer's disease, and Huntington's disease. Understanding the molecular mechanisms underlying NMDAR plasticity could help elucidate the precise contribution of these receptors to normal brain function, and also provide significant insights in developing novel strategies for restoring receptor function in specific disease states.

Public Health Relevance

NMDA receptors mediate excitatory synaptic transmission and play a key role in neural development and brain plasticity. Dysregulation of NMDA receptors has been implicated in a variety of neurological and psychiatric disorders, including ischemia, stroke, epilepsy, schizophrenia, drug addiction, chronic pain, and several neurodegenerative diseases. Understanding how neural activity modulates NMDA receptors under physiological conditions may contribute to the development of novel therapies for ameliorating NMDAR dysfunction in disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH081935-06
Application #
8687904
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (04))
Program Officer
Asanuma, Chiiko
Project Start
2007-12-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$417,500
Indirect Cost
$167,500
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Hou, Hailong; Chávez, Andrés E; Wang, Chih-Chieh et al. (2014) The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function. J Neurosci 34:14006-12
Younts, Thomas J; Castillo, Pablo E (2014) Endogenous cannabinoid signaling at inhibitory interneurons. Curr Opin Neurobiol 26:42-50
Younts, Thomas J; Chevaleyre, Vivien; Castillo, Pablo E (2013) CA1 pyramidal cell theta-burst firing triggers endocannabinoid-mediated long-term depression at both somatic and dendritic inhibitory synapses. J Neurosci 33:13743-57
Hunt, David L; Puente, Nagore; Grandes, Pedro et al. (2013) Bidirectional NMDA receptor plasticity controls CA3 output and heterosynaptic metaplasticity. Nat Neurosci 16:1049-59
Klein, Matthew E; Younts, Thomas J; Castillo, Pablo E et al. (2013) RNA-binding protein Sam68 controls synapse number and local ?-actin mRNA metabolism in dendrites. Proc Natl Acad Sci U S A 110:3125-30
Tomita, Susumu; Castillo, Pablo E (2012) Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors. J Physiol 590:2217-23
Hoge, Gregory J; Davidson, Kimberly G V; Yasumura, Thomas et al. (2011) The extent and strength of electrical coupling between inferior olivary neurons is heterogeneous. J Neurophysiol 105:1089-101
Straub, Christoph; Hunt, David L; Yamasaki, Miwako et al. (2011) Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nat Neurosci 14:866-73
Chavez, Andres E; Chiu, Chiayu Q; Castillo, Pablo E (2010) TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat Neurosci 13:1511-8