Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability

Caldeira, Gladys L.; Inácio, Ângela S.; Beltrão, Nuno; Barreto, Carlos; Rodrigues, Mariana; Rondão, Tiago; Macedo, R.; Gouveia, Raquel; Edfawy, Mohamed; Guedes, Joana; Cruz, B; Louros, Susana R.; Moreira, Irina S.; Peça, João; Carvalho, Ana Luı́sa

doi:10.1038/s41380-022-01487-w

Cited by 10 publications

(7 citation statements)

References 61 publications

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“…However, Tg and KO animals where genes primarily involved in AMPAR trafficking and function are targeted, result in either no change, or significant deficits to learning and memory. For instance, single deletions of most Transmembrane AMPAR regulatory proteins (TARPs) do not show obvious behavioral phenotypes (Letts et al, 2005; Menuz et al, 2008; Milstein and Nicoll, 2009; Rouach et al, 2005), whereas mutations of TARP2 cause learning and memory deficits (Caldeira et al, 2022). Deficits of learning and memory are also observed in knockout animals of AMPAR binding proteins GRIP1 (Tan et al, 2020), GRASP1 (Chiu et al, 2017), LARGE1 (Seo et al, 2018), as well as the PICK1-associated protein ICA69 (Chiu et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Knockout of AMPA receptor binding protein Neuron-Specific Gene 2 (NSG2) enhances associative learning and cognitive flexibility

Zimmerman,

Serrano-Rodriguez,

Wilson

et al. 2024

Preprint

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The vast majority of gene mutations and/or gene knockouts result in either no observable changes, or significant deficits in molecular, cellular, or organismal function. However, in a small number of cases, mutant animal models display enhancements in specific behaviors such as learning and memory. To date, most gene deletions shown to enhance cognitive ability generally affect a limited number of pathways such as NMDA receptor- and translation-dependent plasticity, or GABA receptor- and potassium channel-mediated inhibition. While endolysosomal trafficking of AMPA receptors is a critical mediator of synaptic plasticity, mutations in genes that affect AMPAR trafficking either have no effect or are deleterious for synaptic plasticity, learning and memory. NSG2 is one of the three-member family of Neuron-specific genes (NSG1-3), which have been shown to regulate endolysosomal trafficking of a number of proteins critical for neuronal function, including AMPAR subunits (GluA1-2). Based on these findings and the largely universal expression throughout mammalian brain, we predicted that genetic knockout of NSG2 would result in significant impairments across multiple behavioral modalities including motor, affective, and learning/memory paradigms. However, in the current study we show that loss of NSG2 had highly selective effects on associative learning and memory, leaving motor and affective behaviors intact. For instance, NSG2 KO animals performed equivalent to wild-type C57Bl/6n mice on rotarod and Catwalk motor tasks, and did not display alterations in anxiety-like behavior on open field and elevated zero maze tasks. However, NSG2 KO animals demonstrated enhanced recall in the Morris water maze, accelerated reversal learning in a touch-screen task, and accelerated acquisition and recall on a Trace Fear Conditioning task. Together, these data point to a specific involvement of NSG2 on multiple types of associative learning, and expand the repertoire of pathways that can be targeted for cognitive enhancement.

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Section: Discussionmentioning

confidence: 99%

Knockout of AMPA receptor binding protein Neuron-Specific Gene 2 (NSG2) enhances associative learning and cognitive flexibility

Zimmerman,

Serrano-Rodriguez,

Wilson

et al. 2024

Preprint

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“…Hippocampal CA1 region is important for learning and memory, and its neuronal defects are widely implicated in ID-related neurodevelopmental diseases ( 30 – 32 ). Unexpectedly, loss of KAT6A did not affect CA1 synaptic function.…”

Section: Discussionmentioning

confidence: 99%

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3

Liu,

Fan,

Yang

et al. 2024

Sci. Adv.

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Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A , whose mutations cause KAT6A syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene Rspo2 , encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A syndrome and related neurodevelopmental diseases.

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“…Hippocampal CA1 region is important for learning and memory, and its neuronal defects are widely implicated in ID-related neurodevelopmental diseases ( 30–32 ). Surprisingly, loss of KAT6A did not affect CA1 synaptic function.…”

Section: Discussionmentioning

confidence: 99%

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3

Liu,

Fan,

Yang

et al. 2024

Preprint

View full text Add to dashboard Cite

Intellectual disability (ID) affects ~2% of the general population and is often genetic in origin. ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose de novo heterozygous mutations cause KAT6A Syndrome (or Arboleda-Tham Syndrome), with ID as a common clinical feature. However, the underlying molecular mechanisms remain elusive. Here, we show that haploinsufficiency of Kat6a impairs learning and memory in mice, and specific deletion of Kat6a in excitatory neurons recapitulates the hippocampus-dependent memory deficits. Unexpectedly, KAT6A deficiency results in impaired synaptic structure and plasticity in hippocampal CA3, but not in CA1 region. Combining single-nucleus RNA-sequencing and chromatin analysis, we identify a CA3-enriched gene Rspo2, encoding a Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Moreover, deletion of Rspo2 in excitatory neurons phenocopies the loss of Kat6a, resulting in defective Wnt/β-catenin signaling and synaptic plasticity in CA3, and abnormal cognitive behaviors in mice. Importantly, restoring RSPO2 expression in CA3 pyramidal neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A plays a critical role in regulating synaptic plasticity and memory formation through RSPO2-mediated Wnt signaling in hippocampal CA3, shedding new light on the fundamental mechanisms of ID and providing potential therapeutic targets for the treatment of KAT6A Syndrome and related neurodevelopmental diseases.

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Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability

Cited by 10 publications

References 61 publications

Knockout of AMPA receptor binding protein Neuron-Specific Gene 2 (NSG2) enhances associative learning and cognitive flexibility

Knockout of AMPA receptor binding protein Neuron-Specific Gene 2 (NSG2) enhances associative learning and cognitive flexibility

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3

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