Abstract
SummaryThe generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect. Glypican 4 induces release of the AMPA receptor clustering factor neuronal pentraxin 1 from presynaptic terminals by signaling through presynaptic protein tyrosine phosphatase receptor δ. Pentraxin then accumulates AMPA receptors on the postsynaptic terminal forming functional synapses. Our findings reveal a signaling pathway that regulates synaptic activity during central nervous system development and demonstrates a role for astrocytes as organizers of active synaptic connections by coordinating both pre and post synaptic neurons. As mutations in glypicans are associated with neurological disorders, such as autism and schizophrenia, this signaling cascade offers new avenues to modulate synaptic function in disease.
Highlights
During central nervous system (CNS) development, the formation of neuronal synapses at the right time, in the right place, and of the right strength is crucial to the ongoing function of the brain throughout life
We previously showed that astrocytesecreted glypicans 4 and 6 (Gpc4 and Gpc6) induce active synapse formation by recruiting dendritic GluA1-containing AMPA glutamate receptors (AMPARs) (Allen et al, 2012); the neuronal signaling pathways that underlie this effect have not been determined
retinal ganglion cell neurons (RGCs) are ideal for these studies as they form few synapses when cultured in isolation but profoundly increase synapse number and function when cultured with astrocytes or astrocyte-secreted proteins, including Gpc4-mediated synaptogenesis (Gpc4) (Allen et al, 2012)
Summary
During central nervous system (CNS) development, the formation of neuronal synapses at the right time, in the right place, and of the right strength is crucial to the ongoing function of the brain throughout life. An important family of extracellular regulators are the neuronal pentraxins (NP): NP1, NP2 ( known as NARP), and NPR (Lee et al, 2017; O’Brien et al, 1999; Sia et al, 2007; Xiao et al, 2017; Xu et al, 2003). These secreted glycoproteins bind to AMPARs and stabilize them on dendritic surfaces (O’Brien et al, 1999). In contrast to NP2, which is an immediate early gene whose mRNA is known to be regulated by neuronal activity (Xu et al, 2003), the mechanisms that regulate release of NP1 from neurons are not known
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
