The Requirement of the C-Terminal Domain of GluA1 in Different Forms of Long-Term Potentiation in the Hippocampus Is Age-Dependent

An Liu; Hong Ji; Qiaoyun Ren; Yanghong Meng; Haiwang Zhang; Graham Collingride; Wei Xie; Zhengping Jia

doi:10.3389/fnsyn.2020.588785

The Requirement of the C-Terminal Domain of GluA1 in Different Forms of Long-Term Potentiation in the Hippocampus Is Age-Dependent

Front Synaptic Neurosci. 2020 Oct 30:12:588785. doi: 10.3389/fnsyn.2020.588785. eCollection 2020.

Authors

An Liu¹, Hong Ji¹, Qiaoyun Ren¹, Yanghong Meng², Haiwang Zhang^{2

3}, Graham Collingride², Wei Xie¹, Zhengping Jia^{2

3}

Affiliations

¹ The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, School of Life Science and Technology, Jiangsu Co-Innovation Center of Neuroregeneration, Southeast University, Nanjing, China.
² Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.

Abstract

Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of long-lasting synaptic plasticity widely regarded as the cellular basis for learning and memory. At the CA1 synapse, there are multiple forms of LTP with distinct properties. Although AMPA glutamate receptors (AMPARs) are a key target of LTP expression, whether they are required in all forms of LTP remains unclear. To address this question, we have used our recently developed mouse line, GluA1 ^C2KI , where the c-terminal domain (CTD) of the endogenous GluA1 is replaced by that of GluA2. Unlike traditional GluA1 global or conditional KO mice, GluA1 ^C2KI mice have no changes in basal AMPAR properties or synaptic transmission allowing a better assessment of GluA1 in synaptic plasticity. We previously showed that these mice are impaired in LTP induced by high-frequency stimulation (HFS-LTP), but whether other forms of LTP are also affected in these mice is unknown. In this study, we compared various forms of LTP at CA1 synapses between GluA1 ^C2KI and wild-type littermates by using several induction protocols. We show that HFS-LTP is impaired in both juvenile and adult GluA1 ^C2KI mice. The LTP induced by theta-burst stimulation (TBS-LTP) is also abolished in juvenile GluA1 ^C2KI mice. Interestingly, TBS-LTP can still be induced in adult GluA1 ^C2KI mice, but its mechanisms are altered becoming more sensitive to protein synthesis and the extracellular signal-regulated kinase (ERK) inhibitors compared to wild type (WT) control. The GluA1 ^C2KI mice are also differentially altered in several forms of LTP induced under whole-cell recording paradigms. These results indicate that the CTD of GluA1 is differentially involved in different forms of LTP at CA1 synapse highlighting the complexity and adaptative potential of LTP expression mechanisms in the hippocampus.

Keywords: AMPA receptor; C-terminal domain; ERK; GluA1; high frequency stimulation; long-term potentiation; protein synthesis; theta-burst stimulation.