Wortmannin Attenuates Seizure-Induced Hyperactive PI3K/Akt/mTOR Signaling, Impaired Memory, and Spine Dysmorphology in Rats

Carter, Angela N.; Born, Heather A.; Levine, Amber T.; Dao, An T.; Zhao, Amanda; Lee, Wai Ling; Anderson, Anne E.

doi:10.1523/eneuro.0354-16.2017

Cited by 23 publications

(17 citation statements)

References 40 publications

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“…The progressive deterioration of hippocampal‐dependent trace memory that we found complements studies that have found impairments in contextual memory, spatial memory, and cued recall of amygdala‐dependent memory in delay fear conditioning following an acute seizure . In addition, our follow‐up trace fear conditioning experiments expand on previous studies, which have only examined memory as far out as 40 h after a seizure and indicate that memory impairment persists up to 2 weeks.…”

Section: Discussionsupporting

confidence: 79%

“…There is one study by Carter et al, 2017, that has provided evidence that inhibition of the upstream regulator of mTOR, PI3K, reduces long‐term memory deficits. Inhibiting PI3K 10 min after a seizure by wortmannin leads to a reduction in downstream phospo‐Akt, phospho‐S6 (ser240/244), and a partial rescue of long‐term auditory memory, but no effect on long‐term contextual memory . The lack of full rescue in Carter et al, 2017, may indicate a role for FMRP, which we found to be altered, in seizure‐induced memory impairment.…”

Section: Discussionmentioning

confidence: 55%

“…More recently, studies have shown that a single seizure can produce memory impairment in the absence of chronic pathology. A single seizure prior to learning can impair both hippocampus‐dependent and amygdala‐dependent memory . It is still unclear if and which other types of memory are susceptible to impairment after a seizure.…”

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confidence: 99%

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A single seizure selectively impairs hippocampal‐dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

et al. 2018

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SummaryObjectiveA single brief seizure before learning leads to spatial and contextual memory impairment in rodents without chronic epilepsy. These results suggest that memory can be impacted by seizure activity in the absence of epilepsy pathology. In this study, we investigated the types of memory affected by a seizure and the time course of impairment. We also examined alterations to mammalian target of rapamycin (mTOR) and fragile X mental retardation protein (FMRP) signaling, which modulate elements of the synapse and may underlie impairment.MethodsWe induced a single seizure and investigated hippocampal and nonhippocampal memory using trace fear conditioning, novel object recognition (NOR), and accelerating rotarod to determine the specificity of impairment in mice. We used western blot analysis to examine for changes to cellular signaling and synaptic proteins 1 h, 24 h, and 1 week after a seizure. We also included a histologic examination to determine if cell loss or gross lesions might alternatively explain memory deficits.ResultsBehavioral results indicated that a seizure before learning leads to impairment of trace fear memory that worsens over time. In contrast, nonhippocampal memory was unaffected by a seizure in the NOR and rotarod tasks. Western analysis indicated increased hippocampal phospho‐S6 and total FMRP 1 h following a seizure. Tissue taken 24 h after a seizure indicated increased hippocampal GluA1, suggesting increased α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor expression. Histologic analysis indicated that neither cell loss nor lesions are present after a single seizure.SignificanceThe presence of memory impairment in the absence of damage suggests that memory impairment caused by seizure activity differs from general memory impairment in epilepsy. Instead, memory impairment after a single seizure is associated with alterations to mTOR and FMRP signaling, which leads to a disruption of synaptic proteins involved in consolidation of long‐term memory. These results have implications for understanding memory impairment in epilepsy.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 55%

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A single seizure selectively impairs hippocampal‐dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

et al. 2018

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“…Previous studies have demonstrated that aberrant alterations in the dendritic spine density are commonly observed in brain samples from epilepsy patients and epilepsy animal models (Jiang et al, 1998;Wong and Guo, 2013). Dendritic spine abnormalities might increase the hyperexcitable circuits or intrinsic properties of neurons that might cause seizures, and seizures also result in damage to dendrites and dendritic spines, which might contribute to progressive recurrent seizures, mental disorders, memory disturbances, and other neurological deficits in epilepsy patients (Jimenez-Mateos et al, 2015;Awad et al, 2016;Carter et al, 2017) Previous study suggest that KIF1A mutations that cause hereditary spastic paraplegia are loss-of-function mutations that decrease motility (Esmaeeli Nieh et al, 2015). However, not all mutations are loss-of-function.…”

Section: Discussionmentioning

confidence: 99%

A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity

et al. 2020

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Although genetic factors are considered a main etiology of epilepsy, the causes of genetic epilepsy in the majority of epilepsy patients remain unknown. Kinesin family member 1A (KIF1A), a neuron-specific motor protein that moves along with microtubules, is responsible for the transport of membranous organelles and synaptic vesicles. Variants of KIF1A have recently been associated with hereditary spastic paraplegia (HSP), hereditary sensory and autonomic neuropathy type 2 (HSANII), and intellectual disability. However, mutations in KIF1A have not been detected in patients with epilepsy. In our study, we conducted customized sequencing of epilepsy-related genes of a family with six patients with generalized epilepsy over three generations and identified a rare heterozygous mutation (c.1190C > A, p. Ala397Asp) in KIF1A. Whole-cell recordings from primary cultured neurons revealed that the mutant KIF1A increases the excitatory synaptic transmission but not the intrinsic excitability of neurons, and phenotype testing in zebrafish showed that this rare mutation results in epileptic seizure-like activity. These results provide new evidence demonstrating that KIF1A dysfunction is involved in epileptogenesis.

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“…Class I catalytic isoforms are the most commonly studied class of PI3Ks and are termed p110α, -β, -γ, and -δ (Vanhaesebroeck et al, 2010). While Class I p110-kinases have been predominantly investigated in the context of cancer and the immune system (Vanhaesebroeck et al, 2016), recent research demonstrates an 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;Martín-Peña et al, 2006;Cuesto et al, 2011;Jordán-Álvarez et al, 2012Jordán-Álvarez et al, , 2017Carter et al, 2017). Nevertheless, the role of individual PI3K isoforms in these processes and their contribution to neurological disorders is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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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Wortmannin Attenuates Seizure-Induced Hyperactive PI3K/Akt/mTOR Signaling, Impaired Memory, and Spine Dysmorphology in Rats

Abstract: Visual Abstract

Cited by 23 publications

References 40 publications

A single seizure selectively impairs hippocampal‐dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

A single seizure selectively impairs hippocampal‐dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity

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

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