Presynaptic α2δ1 Regulates Ampar-dependent Synaptic Plasticity, Spatial Memory, and Seizure Susceptibility
Abstract number :
3.049
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2024
Submission ID :
287
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Gerardo Sandoval, B.A. – University of California, Irvine
Ananth Kolli, B.S. – University of California, Irvine
Emily Saavedra, B.S. – University of California, Irvine
Matt Sandoval, B.S. – University of California, Irvine
Javier Diaz-Alonso, PhD – University of California, Irvine
Rationale: AMPA receptors (AMPARs) are the main mediators of fast excitatory synaptic transmission in the mammalian CNS. The regulation of AMPAR abundance, crucial for several synaptic plasticity mechanisms, also determines circuit excitability. Genetic alterations affecting pore-forming AMPAR subunits, but also AMPAR regulatory proteins, can lead to hyperexcitable brain circuits and is a common feature in various forms of epilepsy. AMPAR recruitment to synapses involves a well-synchronized network encompassing both intracellular interactions between AMPAR auxiliary proteins and postsynaptic scaffold proteins promoting AMPAR docking, and as of recent, extracellular mechanisms in the synaptic cleft between AMPARs and putative synaptic cleft proteins. We and other laboratories discovered that the AMPAR amino terminal domain (ATD), which accounts for approximately half of the protein size and protrudes substantially into the synaptic cleft, is essential for AMPAR synaptic trafficking and long-term potentiation (LTP). It is conceivable that the AMPAR ATD may contribute to AMPAR trafficking and transsynaptic positioning through extracellular interactions. Transsynaptic AMPAR alignment may influence synaptic plasticity, but the underlying molecular mechanisms have yet to be identified.
Methods: To identify novel AMPAR ATD-interacting proteins, we conducted proteomic analyses and identified the voltage-gated calcium channel auxiliary subunit α2δ1 as a potential interactor. We decided to further investigate this protein because of its extracellular topology, proximity to glutamate release sites, and association with intellectual disability and epilepsy. Co-immunoprecipitation experiments confirmed a direct interaction between ɑ2δ1 and the AMPAR ATD. We generated Grik4-cre:α2δ1f/f mice (α2δ1∆CA3), which lack α2δ1 in hippocampal field CA3, to study the presynaptic role of α2δ1 at CA3-CA1 synapses using whole-cell patch-clamp electrophysiology in hippocampal slices in combination with biochemical assays and behavioral assessments.
Results: Presynaptic deletion of α2δ1 at CA3-CA1 synapses impairs LTP, but not basal synaptic transmission, in CA1 pyramidal neurons. Consistent with the specificity of our genetic manipulation, α2δ1∆CA3 mice demonstrate a specific impairment in the CA1-dependent dependent object location memory task. Furthermore, we see that CA3-deletion of α2δ1 leads to a substantial decrease in seizure susceptibility (i.e. latency to tonic-clonic seizure), suggesting its involvement in the regulation of synaptic AMPAR content and excitability.
Conclusions:
In summary, we present evidence showing that presynaptic deletion of α2δ1 affects AMPAR synaptic plasticity, memory, and circuit excitability through its interaction with the AMPAR ATD. Our data supports the existence of a transsynaptic regulatory mechanism which contributes to AMPAR synaptic localization and function, influencing the development of hyperexcitable circuits.
Funding:
MH118425 R00 NIH Pathway to Independence Award and NARSAD BBRF Young Investigator Award to JDA. NINDS/NIH Training Grant T32 NS-45540 to GS.
Basic Mechanisms