Functional specialization of different PI3K subtypes in controlling neuronal structure, synaptic plasticity, and cognition

Experience-dependent modifications of synaptic connectivity, called synaptic plasticity, are thought to be the cellular basis
of learning and memory.

Synaptic plasticity of neuronal connections and activity-dependent is fundamental
to supporting brain function and cognitive performance.

Synaptic plasticity and cell growth/survival often rely on common signaling drivers—for example, intracellular signaling of Phosphatidylinositol 3-kinase (PI3K) controls a variety of mechanisms
that mediate neuronal growth, synaptic structure, and plasticity.
These pleiotropic (and sometimes antagonistic) effects driven by PI3K activity may be associated with
the molecular diversity of PI3K.
Class IA PI3Ks is an isodimer composed of regulatory subunits (usually p85α or p85β) and catalytic subunits (p110α, p110β or p110δ) that catalyze the production
of phosphatidylinositol 3,4,5-triphosphate (PIP3) under ligand stimulation.
In the class IA PI3K catalytic subunit, p110α and p110β are widely expressed throughout life, and their deletion can lead to embryonic death
.
It can therefore be assumed that the p110α and p110β subtypes may play a non-redundant role
in the structure, synaptic plasticity, and ultimately cognitive function of mature neurons.

To investigate how these pleiotropic functions integrate at the molecular and cellular levels, and to bypass embryonic lethality, the authors used conditional and regionally restricted gene targeting methods to knock out p110α or p110β (the two main catalytic isoforms of PI3K type I) in the hippocampus of adult mice with neuron-specific virus-delivered Cre expression, and compared different knockout mice using neuron-specific virus-delivered Cre expression
, and compared different knockout mice in combination with proteomics, imaging, electrophysiology, and behavioral assays 。 Based on these experiments, the authors investigated the differential effect of neuronal ablation of p110α or p110β on protein expression profiles, suggesting that the two isotypes have different functions in neurons, with P110α and p110β playing different roles
in synaptic and dendritic maintenance, basal synaptic transmission, and synaptic plasticity.

The results showed that dendrites and postsynaptic structures were almost entirely supported by p110α activity, while p110β controlled neurotransmitter release and long-term inhibition
of metabolic glutamate receptor dependence at the presynaptic terminal.
In addition to these separate functions, p110α and p110β are jointly involved in postsynaptic long-course enhancement
dependent on N-methyl-D-aspartate receptors.
Mice with hippocampal deletion p110α or p110β deletion in adult mice exhibit different behavioral phenotypes in memory and social behavior, further illustrating that this molecular and functional specialization is reflected in different proteomes controlled by each subtype, as well as different behavioral alterations in learning/memory and social abilities
.

Result highlights

Proteomic analysis of mice lacking neurons p110α or p110β showed differences in cellular processes controlled by the two isotypes, suggesting that the P110α and p110β subtypes may play different roles
in synaptic function and intracellular signaling.

The loss of p110α (rather than p110β) impairs the maintenance of dendrites and spine of hippocampal pyramidal neurons
.
Loss of p110α leads to significant remodeling of neuronal and synaptic morphology, major contraction of dendritic dendritic structures and loss of spinous processes, accompanied by enlargement
of remaining postsynaptic structures.
These changes are much
milder in p110β.
This suggests that PI3K-dependent regulation of neuronal morphology and postsynaptic structure is mainly mediated by the p110α subtype
.

Deletion of p110α and p110β leads to vesicle accumulation of presynaptic terminals

p110α and p110β control basal synaptic transmission in opposite directions, and p110α and p110β control different forms of synaptic plasticity
.
During synaptic plasticity, the synaptic site of p110α is confined to the postsynaptic compartment, and p110β has a dual role: it controls neurotransmitter release at the presynaptic terminals, mediates mGluR LTD, and promotes NMDAR-dependent LTP
in the postsynaptic compartment.

Deletion of p110α or p110β in hippocampal neurons in adult mice leads to different behavioral abnormalities
.
Analysis of anxiety, memory, and social behavior in p110α or p110β-deficient mice in control mice and neurons showed that p110αnKO and p110βnKO mice showed higher motor activity in the open field test, but p110α knockout mice showed habituation to the new environment after the first few minutes (reduced motor activity over time).

In contrast, p110β knockout mice remained hyperactive throughout the test period, indicating defective habituation
when p110β was removed.
p110β, not p110α, is necessary for
object recognition memory.
Removal of p110α or p110β caused mice to exhibit impaired behavior at the level of social preference and social memory, as well as impaired working memory or behavioral flexibility, but neither appeared to produce an anxiety effect
.

This provides a well-established review of neuronal morphology and functionality for the functional and functional isolation of PI3K nerve cells
.
This specialization may be related to cognitive function in neurodevelopmental and psychiatric disorders and may pave the way
for new treatment strategies for these neurological disorders.