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.
Highlights
Phosphoinositide 3-kinases (PI3Ks) are essential lipid kinases that signal up- and down-stream of critical cell signaling molecules including multiple growth factors, cytokines and their cognate receptors (Toker and Cantley, 1997; Cantrell, 2001)
PI3Kinase-p110δ Overexpression Impairs Neuronal Development emerging role for PI3K signaling in neurological function, with direct roles for PI3Ks having been identified in axon extension (Cosker and Eickholt, 2007), dendritic complexity, and synaptogenesis (Jaworski et al, 2005; Kumar et al, 2005; MartínPeña et al, 2006; Cuesto et al, 2011; Jordán-Álvarez et al, 2012, 2017; Carter et al, 2017)
Recent studies suggest that the PIK3CD/p110δ catalytic subunit is one such isoform relevant for neurological development and disease, with PIK3CD being associated with increased risk for schizophrenia (Law et al, 2012), and increased expression being identified in patients with schizophrenia or autism spectrum disorder (Law et al, 2012; Poopal et al, 2016; Hood et al, 2019)
Summary
Phosphoinositide 3-kinases (PI3Ks) are essential lipid kinases that signal up- and down-stream of critical cell signaling molecules including multiple growth factors, cytokines and their cognate receptors (Toker and Cantley, 1997; Cantrell, 2001). Recent studies suggest that the PIK3CD/p110δ catalytic subunit is one such isoform relevant for neurological development and disease, with PIK3CD being associated with increased risk for schizophrenia (Law et al, 2012), and increased expression being identified in patients with schizophrenia or autism spectrum disorder (Law et al, 2012; Poopal et al, 2016; Hood et al, 2019). Patients carrying gain-of-function mutations in the PIK3CD gene, termed ‘‘activated PI3K-δ syndrome,’’ are often diagnosed with intellectual delay (Coulter et al, 2017) Together these studies suggest that overexpression of p110δ is relevant to neurological disorders with neurodevelopmental origins. Our findings provide novel insight into how gain-of-function of p110δ may contribute to the etiology of neurodevelopmental disorders
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