Cytosolic PSD-95 interactor alters functional organization of neural circuits and AMPA receptor signaling independent of PSD-95 binding.

Ana R Rodriguez,Bonnie L Firestein,Erin D Anderson,David F Meaney,Nicholas F Vigilante,Kate M O’Neill,Przemyslaw P Mcewan,Barbara F Akum,Munjin Kwon,Tamara M Stawicki

doi:10.1162/netn_a_00173

Abstract

Cytosolic PSD-95 interactor (cypin) regulates many aspects of neuronal development and function, ranging from dendritogenesis to synaptic protein localization. While it is known that removal of postsynaptic density protein-95 (PSD-95) from the postsynaptic density decreases synaptic N-methyl-D-aspartate (NMDA) receptors and that cypin overexpression protects neurons from NMDA-induced toxicity, little is known about cypin’s role in AMPA receptor clustering and function. Experimental work shows that cypin overexpression decreases PSD-95 levels in synaptosomes and the PSD, decreases PSD-95 clusters/μm2, and increases mEPSC frequency. Analysis of microelectrode array (MEA) data demonstrates that cypin or cypinΔPDZ overexpression increases sensitivity to CNQX (cyanquixaline) and AMPA receptor-mediated decreases in spike waveform properties. Network-level analysis of MEA data reveals that cypinΔPDZ overexpression causes networks to be resilient to CNQX-induced changes in local efficiency. Incorporating these findings into a computational model of a neural circuit demonstrates a role for AMPA receptors in cypin-promoted changes to networks and shows that cypin increases firing rate while changing network functional organization, suggesting cypin overexpression facilitates information relay but modifies how information is encoded among brain regions. Our data show that cypin promotes changes to AMPA receptor signaling independent of PSD-95 binding, shaping neural circuits and output to regions beyond the hippocampus.

Highlights

Neurons transfer information to each other via signaling complexes assembled at synapses
Cypin regulates neural circuitry and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signaling cypin overexpression, finding that our simulated model demonstrates a role for AMPA receptors in cypin-promoted changes to neural circuits
These results support a role for cypin in controlling synaptic function at synapses that is distinct from regulation of Postsynaptic density (PSD)-95 function

Summary

Introduction

Neurons transfer information to each other via signaling complexes assembled at synapses. PSD95 contains three PDZ domains, which are protein-protein interaction motifs (Kim & Sheng, 2004) and which bind to multiple receptors and ion channels and their accessory proteins (Cohen et al, 1996; Kim et al, 1995; Kornau et al, 1995) that contain the carboxyl terminal PDZ-binding consensus sequence Thr/Ser-X-Val/Ile-COOH (Kornau et al, 1995; Sheng & Wyszynski, 1997) These PDZ domains serve to aggregate neurotransmitter receptors, such as the NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that are activated by the excitatory neurotransmitter glutamate, and their downstream enzymes, such as neuronal nitric oxide synthase (NOS1, nNOS), promoting subcellular protein compartmentalization and ensuring selective activation of signal transduction cascades at synaptic sites (Scott & Zuker, 1997, 1998). The regulation of PSD-95 expression/degradation, clustering, and localization may play an important role in establishment and maintenance of proper synaptic connections during development and throughout adulthood (Matus, 2000)

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Discussion

Conclusion