Mechanisms of increased hippocampal excitability in the Mashl+/− mouse model of Na+/K+‐<scp>ATP</scp>ase dysfunction

Hunanyan, Arsen; Helseth, Ashley; Abdelnour, Elie; Kherallah, Bassil; Sachdev, Monisha; Chung, Leeyup; Masoud, Melanie; Richardson, Jarrett W.; Li, Qiang; Nadler, J. Victor; Moore, Scott D.; Mikati, Mohamad A.

doi:10.1111/epi.14441

Cited by 43 publications

(30 citation statements)

References 44 publications

(141 reference statements)

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“…Additionally, the Na + /K + ATPase is known to be highly expressed in the hippocampus and impairment in its function has been shown to result in memory deficits . This mouse manifests marked decrease in hippocampal GABAergic fast‐spiking interneuron firing supporting the notion of a GABAergic interneuronopathy in AHC . Also, our finding of more deficiencies in expressive than receptive language is consistent with our recent publication of marked dysfunction in oral motor control in patients with AHC, and with the observations that the frontal lobe is more likely to manifest decreased metabolism on positron emission tomography and atrophy on magnetic resonance imaging than more posterior cortex …”

Section: Discussionsupporting

confidence: 90%

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Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood

Jasien

Bonner

D’Alli

et al. 2018

Develop Med Child Neuro

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Aim To determine the neuropsychological abnormalities that occur in alternating hemiplegia of childhood (AHC) and report on our experience in managing them. Method Patients underwent evaluations according to our standardized AHC pathway. Data were entered into our prospective AHC database and then analyzed. Results Of the cohort of 25 consecutive patients (ages 15mo–42y), eight had initial chief complaints about cognition, 14 language, five attention, and 11 behavior. As compared to population norms means, neuropsychological and behavioral assessment tools (including Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, and Wechsler Intelligence Quotient tests) showed significant impairments in multiple domains: cognition, expressive and receptive language, executive function/attention, and behavior (p<0.05 in all comparisons). Evaluations generated management recommendations in all patients. Twenty had neuropsychiatric diagnoses: 10 attention‐deficit/hyperactivity disorder (ADHD), seven disruptive behavior, and three anxiety disorder. Eight out of nine patients with ADHD who were prescribed medications responded to pharmacotherapy. Interpretation Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. This supports the hypothesis that the underlying AHC pathophysiology involves diffuse neuronal dysfunction. Testing generated recommendations to help manage these difficulties. Patients with AHC also have a range of neuropsychiatric diagnoses, the most common being ADHD which responds to pharmacotherapy. What this paper adds Patients with alternating hemiplegia of childhood (AHC) have developmental difficulties with underlying neuropsychological impairments. The findings in this study are consistent with an underlying AHC pathophysiology which involves diffuse neuronal, probably largely GABAergic, dysfunction. Patients with AHC have a range of neuropsychiatric diagnoses, the most common being attention‐deficit/hyperactivity disorder.

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Section: Discussionsupporting

confidence: 90%

“…Finally, some of the ADHD symptoms may prove to be secondary to sleep apnea given the high frequency of obstructive as well as central sleep apnea in patients with AHC . Symptomatic management of these disorders takes a special importance since disease modified therapy for AHC currently does not exist …”

Section: Discussionmentioning

confidence: 99%

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood

Jasien

Bonner

D’Alli

et al. 2018

Develop Med Child Neuro

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“…Our findings are consistent with the current understanding of the pathophysiology of AHC and with previously published results on the animal models of AHC. Mice carrying mutations that cause AHC in humans frequently demonstrate abnormal behavior and impairments in social interaction . The pathophysiology underlying AHC in these animals is related to increased excitability of principal neurons and decreased firing of GABAergic fast‐spiking parvalbumin‐positive interneurons .…”

Section: Discussionmentioning

confidence: 99%

Social impairments in alternating hemiplegia of childhood

Uchitel

Abdelnour

Boggs

et al. 2020

Develop Med Child Neuro

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Aim To evaluate presence and severity of social impairments in alternating hemiplegia of childhood (AHC) and determine factors that are associated with social impairments. Method This was a retrospective analysis of 34 consecutive patients with AHC (19 females, 15 males; mean age: 9y 7mo, SD 8y 2mo, range 2y 7mo–40y), evaluated with the Social Responsiveness Scale, Second Edition (SRS‐2). Results SRS‐2 scores, indicating level of social impairment, were higher than population means (75, SD 14 vs 50, SD 10, p<0.001). Of these, 27 out of 34 had high scores: 23 severe (>76), four moderate (66–76). All subscale domains, including social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior, had abnormal scores compared to population means (p<0.001). High SRS‐2 scores were associated with the presence of autism spectrum disorder (ASD) and epilepsy (p=0.01, p=0.04), but not with other scales of AHC disease symptomatology. All nine patients who received formal evaluations for ASD, because they had high SRS‐2 scores, were diagnosed with ASD. Interpretation Most patients with AHC have impaired social skills involving multiple domains. ASD is not uncommon. High SRS‐2 scores in patients with AHC support referral to ASD evaluation. Our findings are consistent with current understandings of the pathophysiology of AHC and ASD, both thought to involve GABAergic dysfunction. What this paper adds Most patients with alternating hemiplegia of childhood (AHC) have impaired social skills involving multiple domains. These impairments are significant compared to population means. Most patients with AHC have high Social Responsiveness Scale, Second Edition (SRS‐2) scores. Patients with AHC with high SRS‐2 scores are likely to have autism spectrum disorder.

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“…Li and Langhans, 2015), a proposed mechanism underling EIEE, or perhaps AHC. We were surprised to find that even after 90 million years of divergence, the human and rodent postnatal cortex possess similar single-cell distribution of ATP1A3 , most notably in PV + INs, underscoring the utility of mice as a model for studying excitatory/inhibitory balance(Bøttger et al, 2011), especially in the context of PV IN loss relating to postnatal brain disorders(Hunanyan et al, 2018). On the other hand, while ATP1A3 expression in INs appears to be conserved, differences in circuits and connectivity, and how interneurons shape gene expression differentially could offer pathological differences between species.…”

Section: Discussionmentioning

confidence: 99%

Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Smith

Florio

Akula

et al. 2020

Preprint

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Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function that is catalyzed by the Na,K-ATPase alpha subunit. In vertebrates, four paralogous genes, ATP1A1-4, encode distinct alpha subunit isoforms (a1-a4), three of which (a1, a2, a3) are expressed in the brain, and two (a1, a3) predominantly in neurons. The a3 isoform, encoded by ATP1A3, is critical to neuronal physiology, and a growing spectrum of neurological diseases are associated with ATP1A3 pathogenic variants, with ages of onset ranging from early childhood to adulthood. Here, we describe ATP1A3 variants encoding dysfunctional a3 subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we established a transcriptional atlas of ATP1A3 expression during cortical development using mRNA in situ hybridization and transcriptomic profiling of ~125,000 individual cells with single-cell RNA sequencing (Drop-Seq) from various areas of the midgestational human neocortex. We find that fetal expression of ATP1A3 is restricted to a subset of excitatory neurons carrying transcriptional signatures of neuronal activity and maturation characteristic of the developing subplate. Furthermore, by performing Drop-Seq on ~52,000 nuclei from four different areas of an infant human neocortex, we show that ATP1A3 expression persists throughout early postnatal development, not only within excitatory neurons across all cortical layers, but also and more predominantly in inhibitory neurons, with specific enrichment in fast-spiking basket cells. In addition, we show that ATP1A3 expression, both in fetal and postnatal neurons, tends to be higher in frontal cortical areas than in occipital areas, in a pattern consistent with the rostro-caudal maturation gradient of the human neocortex. Finally, we discover distinct co-expression patterns linking catalytic α subunit isoforms (ATP1A1,2,3) and auxiliary isoforms (ATP1B1,2,3), suggesting the ATPase pump may form non-redundant, cell-type specific α-β combinations. Together, the importance of the developmental phenotypes and dynamic expression patterns of ATP1A3 point to a key role for a3 in the development and function of human cortex.

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Mechanisms of increased hippocampal excitability in the Mashl^+/− mouse model of Na⁺/K⁺‐ATPase dysfunction

Cited by 43 publications

References 44 publications

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood

Social impairments in alternating hemiplegia of childhood

Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

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Mechanisms of increased hippocampal excitability in the Mashl+/− mouse model of Na+/K+‐ATPase dysfunction

Cited by 43 publications

References 44 publications

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood

Social impairments in alternating hemiplegia of childhood

Role for the Na+/K+ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Contact Info

Product

Resources

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Mechanisms of increased hippocampal excitability in the Mashl^+/− mouse model of Na⁺/K⁺‐ATPase dysfunction

Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex