Synapses are the fundamental functional units of the nervous system, but the molecular and cellular interactions that regulate their establishment are largely unknown. Studies using purified retinal ganglion cell neurons (RGCs) showed that astrocytes secrete signals such as thrombospondins that strongly induce excitatory synapse formation. In our preliminary studies, we identified another astrocyte-secreted synaptogenic protein, hevin. Addition of hevin to purified RGC cultures robustly stimulates excitatory synaptogenesis. Moreover, Hevin-null mice have significantly less excitatory synapses that present striking structural defects suggesting that hevin is required for the formation and morphological maturation of synapses in vivo. Astrocytes also express a close homolog of hevin called SPARC. Intriguingly, SPARC is not synaptogenic but specifically inhibits hevin-induced synaptogenesis. These data show for the first time that astrocytes regulate synaptic connectivity not only by stimulating, but also by inhibiting synaptogenesis. Our results signify the exciting possibility that astrocytes, through the regulation of relative levels of hevin and SPARC, can actively control the development and function of synaptic networks in the developing and adult brain. How hevin induces synapse formation and the nature of SPARC's antagonistic function are unknown. Therefore, our objective here is to unravel a novel molecular mechanism of regulation of synaptic development and maintenance by astrocytes through hevin/SPARC signaling. In this application, we will first test the hypothesis that hevin and SPARC regulate synaptic morphology (Aim 1) and formation of dendritic spine synapses in vivo (Aim 2). Second, we will determine the contribution of hevin/SPARC signaling to synaptic function in vivo (Aim 2). Third, we will test the hypothesis that hevin mediates synaptogenesis through interactions with the trans-synaptic adhesion molecules neurexins and neuroligins, whereas SPARC antagonizes hevin by competing for hevin-binding to neuroligins (Aim 3). These studies are important since they will provide new insights into the control of formation, maintenance and function of synapses by astrocytes. These new insights will have a significant positive impact by advancing our molecular and cellular understanding of astrocyte-neuron interactions that orchestrate central nervous system development and function. A deeper mechanistic understanding of synapse formation and how astrocytes participate in this process will lead to the development of innovative approaches to prevent or cure neurological disorders such as autism, depression and addiction.

Public Health Relevance

The proposed study aims to advance our understanding of astrocyte-neuron interactions that orchestrate central nervous system development and function. Understanding how synaptogenesis is regulated is crucial for understanding how our brains are sculpted during development, and how we learn and remember as adults. In addition, knowledge on how synaptogenesis can go awry is required for development of new prevention and treatment strategies against disorders that stem from dysregulated synapse formation such as Alzheimer's disease, epilepsy, autism and drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA031833-03
Application #
8654325
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Wu, Da-Yu
Project Start
2012-06-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$348,120
Indirect Cost
$123,120
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Park, John; Yu, Yanhui Peter; Zhou, Chun-Yi et al. (2016) Central Mechanisms Mediating Thrombospondin-4-induced Pain States. J Biol Chem 291:13335-48
Stogsdill, Jeff A; Eroglu, Cagla (2016) The interplay between neurons and glia in synapse development and plasticity. Curr Opin Neurobiol 42:1-8
Singh, Sandeep K; Stogsdill, Jeff A; Pulimood, Nisha S et al. (2016) Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin. Cell 164:183-96
Risher, Mary-Louise; Fleming, Rebekah L; Risher, W Christopher et al. (2015) Adolescent intermittent alcohol exposure: persistence of structural and functional hippocampal abnormalities into adulthood. Alcohol Clin Exp Res 39:989-97
Chung, Won-Suk; Allen, Nicola J; Eroglu, Cagla (2015) Astrocytes Control Synapse Formation, Function, and Elimination. Cold Spring Harb Perspect Biol 7:
Risher, Mary-Louise; Sexton, Hannah G; Risher, W Christopher et al. (2015) Adolescent Intermittent Alcohol Exposure: Dysregulation of Thrombospondins and Synapse Formation are Associated with Decreased Neuronal Density in the Adult Hippocampus. Alcohol Clin Exp Res 39:2403-13
Risher, W Christopher; Patel, Sagar; Kim, Il Hwan et al. (2014) Astrocytes refine cortical connectivity at dendritic spines. Elife 3:
Risher, W Christopher; Ustunkaya, Tuna; Singh Alvarado, Jonnathan et al. (2014) Rapid Golgi analysis method for efficient and unbiased classification of dendritic spines. PLoS One 9:e107591
McKinstry, Spencer U; Karadeniz, Yonca B; Worthington, Atesh K et al. (2014) Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J Neurosci 34:9455-72
Wan, Yehong; Ade, Kristen K; Caffall, Zachary et al. (2014) Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder. Biol Psychiatry 75:623-30

Showing the most recent 10 out of 12 publications