APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

Pirone, Antonella; Alexander, Jonathan; Lau, Lauren A.; Hampton, David W.; Zayachkivsky, Andrew; Yee, Amy S.; Yee, Audrey S.; Jacob, Michele H.; Dulla, Chris G.

doi:10.1016/j.nbd.2016.11.002

Cited by 35 publications

(44 citation statements)

References 59 publications

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“…Adenomatous polyposis coli (APC) is a negative regulator of β-catenin/Wnt signaling. Interestingly, multiple human mutations that cause IS involve proteins that modulate, or are modulated by, β-catenin signaling (see Pirone et al for a summary [32]). In line with a hyper-excitation phenotype, genetically removing APC from excitatory forebrain neurons using CamKII-cre results in increased dendritic spines on hippocampal CA1 neurons, increased excitatory neurotransmission, and autistic-like behavior in adults (31).…”

Section: Apc Cko Mouse Modelmentioning

confidence: 99%

Utilizing Animal Models of Infantile Spasms

Dulla

2018

Epilepsy Curr

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Infantile spasms are a devastating epileptic encephalopathy characterized by early life spasms and later seizures. Clinical outcomes of infantile spasms are poor and therapeutic options are limited with significant adverse effects. Therefore, new strategies to treat infantile spasms are of the utmost importance. Animals models of infantile spasms are a critical component of developing new therapies. Here, we review current chronic animal models of infantile spasms and consider future advances that may help improve patient care, as well as our scientific understanding of this debilitating disease.

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Section: Apc Cko Mouse Modelmentioning

confidence: 99%

Utilizing Animal Models of Infantile Spasms

Dulla

2018

Epilepsy Curr

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“…Several animal models of IS or WS or epileptic spasms have been developed [reviewed in (Galanopoulou & Moshe 2015); also see (Dube, Molet, Singh-Taylor, Ivy, Maras & Baram 2015, Pirone, Alexander, Lau, Hampton, Zayachkivsky, Yee et al 2016)]. The investigation of inflammatory pathways in IS has been done so far in the multiple-hit rat model, which will be described below.…”

Section: Does Activation Of the Inflammatory Pathways In The Brainmentioning

confidence: 99%

Inflammation in Epileptic Encephalopathies

Shandra

Moshé

Galanopoulou

2017

Stress and Inflammation in Disorders

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West syndrome (WS) is an infantile epileptic encephalopathy (EE) that manifests with infantile spasms, hypsarrhythmia (in ~60% of infants) and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12–15%) or of unknown origin. The current treatment options include hormonal treatment [adrenocorticotropic hormone (ACTH) and high dose steroids], the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate pro-inflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of West syndrome? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

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“…We found that Tsc1 GFAP CKO mice did have a reduced threshold and increased frequency of NMDA‐induced spasms, suggesting an increased propensity for spasms, although no spontaneous spasms were observed on subsequent days beyond the acute period after NMDA injection. Other “two‐hit” approaches, such as combining an inflammatory insult or other genetic mutations with Tsc1 GFAP CKO mice, could potentially be used to generate a chronic model of infantile spasms 33,39,40 …”

Section: Discussionmentioning

confidence: 99%

Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a mouse model of tuberous sclerosis complex

et al. 2020

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Objective: Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Seizures in TSC typically first present in infancy or early childhood, including focal seizures and infantile spasms. Infantile spasms in TSC are particularly characteristic in its strong responsiveness to vigabatrin. Although a number of mouse models of epilepsy in TSC have been described, there are very limited electroencephalographic (EEG) or seizure data during the preweanling neonatal and infantile-equivalent mouse periods. Tsc1 GFAP CKO mice are a well-characterized mouse model of epilepsy in TSC, but whether these mice have seizures during early development has not been documented.The objective of this study was to determine whether preweanling Tsc1 GFAP CKO mice have developmental EEG abnormalities or seizures, including spasms. Methods: Longitudinal video-EEG and electromyographic recordings were performed serially on Tsc1 GFAP CKO and control mice from postnatal days 9-21 and analyzed for EEG background abnormalities, sleep-wake vigilance states, and spontaneous seizures. Spasms were also induced with varying doses of N-methyl-Daspartate (NMDA). Results: The interictal EEG of Tsc1 GFAP CKO mice had excessive discontinuity and slowing, suggesting a delayed developmental progression compared with control mice.Tsc1 GFAP CKO mice also had increased vigilance state transitions and fragmentation. Tsc1 GFAP CKO mice had spontaneous focal seizures in the early neonatal period and a reduced threshold for NMDA-induced spasms, but no spontaneous spasms were observed. Significance: Neonatal Tsc1 GFAP CKO mice recapitulate early developmental aspects of EEG abnormalities, focal seizures, and an increased propensity for spasms.This mouse model may be useful for early mechanistic and therapeutic studies of epileptogenesis in TSC. K E Y W O R D SEEG, electroencephalography, epilepsy, infantile spasms, seizure, tuberous sclerosis 880 | RENSING Et al.

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APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

Cited by 35 publications

References 59 publications

Utilizing Animal Models of Infantile Spasms

Utilizing Animal Models of Infantile Spasms

Inflammation in Epileptic Encephalopathies

Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a mouse model of tuberous sclerosis complex

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