PI3Kinase-p110δ Overexpression Impairs Dendritic Morphogenesis and Increases Dendritic Spine Density

Abstract

Activity and expression of the phosphoinositide 3-kinase (PI3K) catalytic isoform, PIK3CD/p110δ, is increased in schizophrenia, autism, and intellectual delay and pro-cognitive preclinical efficacy of p110δ-inhibition has been demonstrated in pharmacological, genetic, and developmental rodent models of psychiatric disorders. Although PI3K signaling has been implicated in the development and function of neurons and glia; isoform-specific roles of the individual PI3Ks are less clear and the biological effects of increased p110δ on neuronal development are unknown. Since the pathobiological direction of p110δ changes in neurodevelopmental disorders are increased expression and activity, we hypothesized that overexpression of p110δ would impact measures of neuronal development and maturation relevant to connectivity and synaptic transmission. p110δ overexpression in primary rat hippocampal cultures significantly reduced dendritic morphogenesis and arborization and increased immature and mature dendritic spine densities, without impacting cell viability, soma size, or axon length. Together, our novel findings demonstrate the importance of homeostatic regulation of the p110δ isoform for normative neuronal development and highlight a potential pathophysiological mechanism of association to disorders of neurodevelopment.

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

“…While our data suggested a role of PIK3CD GOF on behaviour, the precise function of PI3Kδ in the brain remains elusive. In mice, p110δ has been found in brain and spinal cord, and proposed to have a role in neuronal morphology ( Nieuwenhuis et al., 2020 ; Eickholt et al., 2007 ; Hood et al., 2020 ; Schmidt et al., 2014 ). Although the expression pattern of human PIK3CD follows a similar distribution as in mice (Allen Human Brain Atlas (2010)), reports of its non-immunological functions are scarce, with only a few studies implicating this isoform in schizophrenia and autism ( Hood et al., 2019 ; Poopal et al., 2016 ; Law et al., 2012 ).…”

“…Accordingly, mutations along this pathway have been commonly associated with neurodevelopmental and neuropsychiatric disorders ( Costa-Mattioli and Monteggia, 2013 ). Although few studies have focused on the specific role of distinct PI3K isoforms in the CNS, PI3Kδ has been proposed to regulate soma size, dendritic complexity and spine number ( Nieuwenhuis et al., 2020 ; Hood et al., 2020 ; Schmidt et al., 2014 ), suggesting a contributing role in neuronal development. Notably, 19–31% of APDS patients were reported to exhibit neurodevelopmental delay ( Coulter et al., 2017 ; Elkaim et al., 2016 ).…”

Functional specialization of different PI3K isoforms for the control of neuronal architecture, synaptic plasticity, and cognition

“…However, PI3K has also been associated with long-term depression (LTD), most consistently when induced by metabotropic glutamate receptors (mGluRs) (17)(18)(19) and by NMDARs (20,21). Together with these established roles in synaptic plasticity, the PI3K pathway drives neuronal growth and structural plasticity during synaptogenesis and neuronal development, exerting direct effects on dendritic complexity, spine number, and shape (22)(23)(24)(25)(26)(27)(28)(29).…”

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

“…Accordingly, mutations along this pathway have been commonly associated with neurodevelopmental and neuropsychiatric disorders (21). Although few studies have focused on the specific role of distinct PI3K isoforms in the CNS, PI3Kδ has been proposed to regulate soma size, dendritic complexity and spine number (12,22,23), suggesting a contributing role towards neuronal morphology. Interestingly, 19-31% of APDS patients were reported to exhibit neurodevelopmental delay (8,9).…”

“…GOF mice presented with altered patterns of locomotion and repetitive behaviours, features reminiscent of symptoms found in individuals with ASD(49,64).While our data supported a role of PIK3CD GOF on behaviour, the precise function of PI3Kδ in the brain remains elusive. In mice, p110δ has been found in brain and spinal cord, and proposed to have a role in neuronal morphology(12,17,22,23). Although the expression pattern of human PIK3CD follows a similar distribution as in mice (Allen Human Brain Atlas (2010)), reports of its non-immunological functions are scarce, with only a few studies implicating this isoform in schizophrenia and autism(18,24,65).…”