Dataset Information

PTP? Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses.

ABSTRACT: Leukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. In the current study, we analyzed the synaptic role of PTP? using newly generated, single conditional knockout (cKO) mice targeting PTP?. We found that the number of synapses was reduced in PTP? cKO cultured neurons in association with impaired excitatory synaptic transmission, abnormal vesicle localization, and abnormal synaptic ultrastructure. Strikingly, loss of presynaptic PTP? reduced neurotransmitter release prominently at excitatory synapses, concomitant with drastic reductions in excitatory innervations onto postsynaptic target areas in vivo. Furthermore, loss of presynaptic PTP? in hippocampal CA1 pyramidal neurons had no impact on postsynaptic glutamate receptor responses in subicular pyramidal neurons. Postsynaptic PTP? deletion had no effect on excitatory synaptic strength. Taken together, these results demonstrate that PTP? is a bona fide presynaptic adhesion molecule that controls neurotransmitter release and excitatory inputs.

SUBMITTER: Han KA

PROVIDER: S-EPMC7284068 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses.

Han Kyung Ah KA Lee Hee-Yoon HY Lim Dongseok D Shin Jungsu J Yoon Taek Han TH Lee Chooungku C Rhee Jeong-Seop JS Liu Xinran X Um Ji Won JW Choi Se-Young SY Ko Jaewon J

iScience 20200528 6

Leukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. In the current study, we analyzed the synaptic role of PTPσ using newly generated, single conditional knockout (cKO) mice targeting PTPσ. We found that the number of synapses was reduced in PTPσ cKO cultured neurons in association with impaired excitatory synaptic transmission, abnormal vesicl ...[more]

PMID: 32516721

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Project description:Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are hub proteins that organize excitatory and inhibitory synapse development through binding to various extracellular ligands. Here, we report that knockdown (KD) of the LAR-RPTP family member PTP? reduced excitatory synapse number and transmission in cultured rat hippocampal neurons, whereas KD of PTP? produced comparable decreases at inhibitory synapses, in both cases without altering expression levels of interacting proteins. An extensive series of rescue experiments revealed that extracellular interactions of PTP? with Slitrks are important for excitatory synapse development. These experiments further showed that the intracellular D2 domain of PTP? is required for induction of heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic machinery assembly. Consistent with this, double-KD of liprin-?2 and -?3 or KD of PTP? substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, PTP?-mediated heterologous synapse formation activity. We propose a synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized retrograde signaling cascades, in which both extracellular and intracellular mechanisms are critical in orchestrating distinct synapse types.SIGNIFICANCE STATEMENT In this study, we sought to test the unproven hypothesis that PTP? and PTP? are required for excitatory and inhibitory synapse formation/transmission, respectively, in cultured hippocampal neurons, using knockdown-based loss-of-function analyses. We further performed extensive structure-function analyses, focusing on PTP?-mediated actions, to address the mechanisms of presynaptic assembly at excitatory synaptic sites. Using interdisciplinary approaches, we systematically applied a varied set of PTP? deletion variants, point mutants, and splice variants to demonstrate that both extracellular and intracellular mechanisms are involved in organizing presynaptic assembly. Strikingly, extracellular interactions of PTP? with heparan sulfates and Slitrks, intracellular interactions of PTP? with liprin-? and its associated proteins through the D2 domain, as well as distinct substrates are all critical.

Dataset Information

PTP? Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses.

Publications

PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses.

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