Role of PI3-Kinase regulatory subunit (p85) isoforms in synaptic plasticity
Title (trans.)
Papel de las isoformas de la subunidad reguladora de PI3-kinasa (p85) en plasticidad sinápticaAuthor
López García, SergioAdvisor
Esteban García, José AntonioEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Oncológicas (CNIO)Date
2023-02-24Subjects
Neuronas; Plasticidad sináptica; Electrofisiología; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 24-02-2023Esta tesis tiene embargado el acceso al texto completo hasta el 24-08-2024

Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Learning and memory are widely thought to rely on synaptic plasticity, that is the ability
of neurons to undergo activity-dependent modifications in the strength of synaptic
transmission. This phenomenon contributes to modify the existing neuronal connections
by changing the postsynaptic number/function of neurotransmitter receptors or the
amount/probability of presynaptic neurotransmitter release. These functional aspects of
synaptic plasticity (functional synaptic plasticity) are often accompanied by structural
changes in dendritic spines (structural synaptic plasticity). However, the underlying
molecular mechanisms connecting functional and structural synaptic plasticity remain
poorly defined.
Class I Phosphatidylinositol-3-Kinases (PI3Ks) constitute a complex family of enzymes
formed by a p110 catalytic (p110α, p110β, p110γ, p110δ) and a p85 regulatory (p85α,
p55α, p50α, p55γ, p85β) subunit, with important roles in several processes including
synaptic plasticity and cognitive function. Moreover, p85 subunits also exist in a free
p110-independent state. Several studies have focused on the requirement of PI3K
catalytic activity for synaptic plasticity. However, the differential interactions and
contributions of the PI3K regulatory isoforms (free or bound to p110s) to the functional
and structural aspects of synaptic plasticity are still unknown.
To address this issue, we have carried out loss-of-function (RNA interference) of specific
p85 isoforms in rat hippocampal slices. After specific knockdown of p85α or p85β, most
PI3K complexes are detected as heterodimers of p110 interacting with the alternative
p85 isoform. In this manner, we can assess the function of p110/p85α versus p110/p85β
forms of PI3K, without altering global amount of p110 heterodimers.
Our electrophysiology experiments with organotypic hippocampal slices demonstrate
that neither p85α nor p85β are required for mGluR-dependent long-term depression
(LTD). In contrast, p85α (and not p85β) is critically required for NMDAR-dependent longterm
potentiation (LTP). In addition, using live-cell imaging experiments, we show that
p85α is also required for cofilin recruitment into spines after LTP induction. Interestingly,
removal of p85β enhances both processes (synaptic potentiation and cofilin recruitment),
possibly because of the larger contribution of p110/p85α heterodimers under these
conditions. Moreover, we have detected that the small GTPases Rac1 and Cdc42
interact preferentially with the BH domain of p85α, as compared to p85β. In agreement
with this biochemical observation, p85α is required for Rac1 activation triggered by PI3K
activity, and for actin polymerization in dendritic spines after LTP induction. Thus, we
propose a mechanism for p85α to modulate actin dynamics during spine structural
plasticity through its specific interaction with Rac1.
The results in this PhD thesis show that the regulatory subunits provide functional
specializations to PI3Ks, with a preponderant role of p85α in synaptic plasticity,
particularly for actin dynamics during long-term synaptic potentiation
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