Reelin regulates neuronal excitability through STriatal enriched protein tyrosine phosphatase (STEP61) and calcium permeable AMPARs in an NMDAR-dependent manner

Murat S. Durakoglugil, Catherine R. Wasser, Connie H. Wong, Inga Pohlkamp, Xunde Xian, Courtney Lane-Donovan, Katja Fritschle, Lea Naestle, Joachim Herz

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Aβ oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD, a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal enriched tyrosine phosphatase (STEP61). Reelin is a neuromodulator that signals through ApoE receptors to protect the synapse against Aβ toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aβoligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP61, prevents the dephosphorylation of GluA2 and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca2+-permeable GluA2-lacking AMPA receptors along with higher STEP61 levels, resulting in occlusion of DHPG-induced-LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.

Original languageEnglish (US)
JournalJournal of Neuroscience
Volume41
Issue number35
DOIs
StatePublished - Sep 1 2021

ASJC Scopus subject areas

  • Neuroscience(all)

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