Immature excitatory synapses in the perinatal brain contain high release probability (Pr) presynaptic terminals coupled to postsynaptic specializations with GluN2B subunit-containing NMDA receptors (hi-Pr, hi-GluN2B synapses). For over two decades, we have known that these immature synapses mature in an activity- dependent manner to low-Pr, low-GluN2B synapses, but the mechanisms that coordinate this transition, why it occurs, and how it contributes to circuit plasticity and stability remain controversial and are fundamental unanswered questions. Addressing these issues will identify basic mechanisms that control synapse development and that may be disrupted in neurodevelopmental and psychiatric disorders. Disruption of the Arg/Abl2 kinase in mice yields a population of hi-Pr, hi-GluN2B synapses that persist into early adulthood. The persistence of these immature synapses drives a >40% net loss of hippocampal synapses between postnatal day (P) 21 and P42, and impairs synaptic plasticity and behavior. Building on these findings, we will identify new regulators of synapse maturation, and determine how they regulate synaptic plasticity and stability.
In Aim 1, we will identify the cell surface receptors that activate Arg to coordinate the maturation from hi-Pr, hi- GluN2B synapses to low-Pr, low-GluN2B synapses. We provide preliminary data that integrin ?3?1 adhesion receptor and platelet-derived growth factor receptor ? (PDGFR?) act upstream of Arg to control synapse function and stability. We will use selective gene inactivation in the pre- and postsynaptic neurons along with genetic epistasis and rescue experiments to address how and where these receptors interact with Arg and each other to regulate Pr and postsynaptic GluN2B levels.
In Aim 2, we will elucidate how Arg mediates GluN2B downregulation at the synapse. Arg-mediated signaling is critical to downregulate GluN2B during maturation. We identified the SHP2 tyrosine phosphatase and the NMDAR-associated protein BRAG1, both mutated in intellectual disability, as likely functional links between Arg and developmental GluN2B downregulation. We will use biochemical, cell-based, and genetic approaches to test how Arg interacts with SHP2 and BRAG1 to downregulate GluN2B function.
In Aim 3, we will characterize how immature and mature synapses differentially contribute to plasticity and stability. We will use patterned glutamate uncaging at single synapses to test whether hi-Pr, hi-GluN2B and low-Pr, low-GluN2B synapses have altered ability to undergo long-term potentiation (LTP) and long-term depression (LTD) in arg?/? mice. We will use in vivo imaging to examine how enlarged dendritic spines at hi- Pr, hi-GluN2B cortical synapses in arg?/? mice differ from normal spines in their plasticity and stability. Our studies will elucidate the mechanisms by which receptors act through Arg and its downstream targets to control Pr and NMDAR composition during synapse maturation. Disruption of these mechanisms may underlie the defects in synapse development, plasticity, and stability in intellectual disability and other brain disorders.

Public Health Relevance

The connections between nerve cells, called synapses, do not form or function properly in the brains of individuals with autism and intellectual disability, and become destabilized in psychiatric diseases and neurodegenerative diseases. We have discovered a signaling network that controls synapse maturation and have shown that disruption of this network in mice causes significant synapse loss and defects in learning, memory, and other behaviors. We will determine how this signaling network regulates synapse maturation to preserve the proper function of nerve circuits and their ability to support learning and memory.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Leenders, Miriam
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Levy, Aaron D; Xiao, Xiao; Shaw, Juliana E et al. (2018) Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell Rep 24:1523-1535
Kim, So-Youn; Nair, Devi M; Romero, Megan et al. (2018) Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. Cell Death Differ :
Jacobsen, Freja Aksel; Scherer, Alexander N; Mouritsen, Jeppe et al. (2018) A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation. J Neuroimmune Pharmacol 13:265-276
Scherer, Alexander N; Anand, Neha S; Koleske, Anthony J (2018) Cortactin stabilization of actin requires actin-binding repeats and linker, is disrupted by specific substitutions, and is independent of nucleotide state. J Biol Chem 293:13022-13032
Zhang, Ke; Lyu, Wanqing; Yu, Ji et al. (2018) Abl2 is recruited to ventral actin waves through cytoskeletal interactions to promote lamellipodium extension. Mol Biol Cell 29:2863-2873
Yamani, Amnah; Wu, David; Waggoner, Lisa et al. (2018) The vascular endothelial specific IL-4 receptor alpha-ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions. J Allergy Clin Immunol 142:1159-1172.e5
Chang, Jeremy T; Higley, Michael J (2018) Potassium channels contribute to activity-dependent regulation of dendritic inhibition. Physiol Rep 6:e13747