Transcription of PIK3CD in human brain and schizophrenia: regulation by proinflammatory cytokines

Hood, Veronica; Berger, Ralph; Freedman, Robert; Law, Amanda J.

doi:10.1093/hmg/ddz144

Cited by 15 publications

(13 citation statements)

References 45 publications

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“…In the p110δ E1020K murine model, we detected more subtle phenotypic alterations. Consistent with this hypothesis, recent studies found more PIK3CD transcripts in human foetal brain than in adult samples (18) and distributed expression of PIK3CD in the developing mouse brain (66). Combined with the fact that PI3Kδ lies upstream of the mTOR pathway, a signalling hub that is highly active during brain development and often found to be dysregulated in neurodevelopmental disorders (19,67,68), this expression suggests that PIK3CD plays a still unexplored role in the modulation of brain development, adding to the growing body of evidence pointing to a critical period for ASD development (52,69).…”

Section: Discussionsupporting

confidence: 56%

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

Serra

Manusama

Kaiser

et al. 2021

Preprint

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The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signalling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.

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Section: Discussionsupporting

confidence: 56%

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

Serra

Manusama

Kaiser

et al. 2021

Preprint

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“…Phosphoinositide 3-kinases (PI3Ks) are modulators of cellular membrane lipids involved in signaling and trafficking events. In the brain, PI3K␦ is expressed in neurons and microglia (Eickholt et al, 2007;Low et al, 2014;Hood et al, 2019). Despite its established role in controlling functions in autoimmunity and inflammation (Okkenhaug and Vanhaesebroeck, 2003;Ali et al, 2014), the role of PI3K␦ in neurons remains largely unknown, with the effects of inhibiting this isoform in the context of neurological disorders also remaining unexplored.…”

Section: Introductionmentioning

confidence: 99%

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

et al. 2019

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Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-␤ (A␤) peptide. Accumulation of A␤, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110␦ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APP swe /PS1 ⌬E9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3K␦ (␦ D910A) had reduced A␤ peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3K␦ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted A␤ peptide. Importantly, APP/PS1/␦ D910A mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3K␦ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.

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“…PI3K signaling is essential for a wide range of neurobiological functions, with an emerging focus on the individual roles of PIK3 catalytic subunits in disorders of neurodevelopment (Gross and Bassell, 2014). Specifically, the Class I PIK3 catalytic subunit p110δ has drawn attention for the genetic association to psychiatric disorders, increased expression in schizophrenia, autism and intellectual delay, as well as an emerging novel target for antipsychotic drug development (Marder et al, 2011;Law et al, 2012;Rico, 2012;Papaleo et al, 2016;Poopal et al, 2016;Coulter et al, 2017;Hood et al, 2019). While the neuronal consequences of p110δ inhibition have begun to be addressed, the impact of clinically-relevant overexpression of p110δ has not been explored.…”

Section: Discussionmentioning

confidence: 99%

“…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). Moreover, 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).…”

Section: Introductionmentioning

confidence: 99%

“…To date, the cellular mechanisms of how increased p110δ expression contributes to schizophrenia, autism or intellectual disability is unknown. Recent work has identified the expression of PIK3CD in the brain and functional roles within the central nervous system (CNS) have begun to be uncovered Law et al, 2012;Low et al, 2014;Schmidt et al, 2014;Papaleo et al, 2016;Hood et al, 2019). While inhibition studies implicate p110δ in aspects of neuronal development Low et al, 2014;Schmidt et al, 2014), a significant gap in knowledge remains as to the impact of increased p110δ on the development of mammalian neuronal morphology, which is of direct relevance to the role of p110δ in diverse neurodevelopmental disorders.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Hood

Paterson

Law

2020

Front. Mol. Neurosci.

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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.

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Transcription of PIK3CD in human brain and schizophrenia: regulation by proinflammatory cytokines

Cited by 15 publications

References 45 publications

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

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

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

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

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