Activation of Rac1 Has an Opposing Effect on Induction and Maintenance of Long-Term Potentiation in Hippocampus by Acting on Different Kinases

Cui, Dongyang; Jiang, Xiaodong; Chen, Ming; Sheng, Huan; Shao, Da; Yang, Li; Guo, Xinli; Wang, Yingqi; Lai, Bin; Zheng, Ping

doi:10.3389/fnmol.2021.720371

Cited by 2 publications

(2 citation statements)

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“…Trio -deficient excitatory neurons are unable to undergo long-term potentiation (LTP) in mouse brain slices (25), which is crucial for working memory in mammals. Notably, Rac1 has important roles in LTP: transient Rac1 activation increases synaptic AMPAR clustering required for LTP induction, while Rac1 inactivation is required for LTP maintenance (110–112). Both +/K1431M and +/K1918X L5 PNs exhibited deficiencies in LTP induction.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, we did not observe reduced PV+ interneuron numbers in the motor cortex in any Trio variant mice, suggesting that Trio variants may impact the number of inhibitory synapses or transmission properties Trio-deficient excitatory neurons are unable to undergo long-term potentiation (LTP) in mouse brain slices(19), which is crucial for working memory in mammals. During LTP ability of Rac1 suggested to be transiently activated and deactivated to regulate AMPAR(96)(97)(98). Both +/…”

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confidence: 99%

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Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Ishchenko,

Jeng,

Feng

et al. 2024

Preprint

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Heterozygosity for rare genetic variants inTRIOis associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal migration, synapse development and function. It remains unclear whether and how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we elucidate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ), and+/M2145T(bipolar disorder, BPD) – impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. ASD- and SCZ-linkedTriovariants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although dendritic spine density and synaptic ultrastructure were only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity including excitatory/inhibitory imbalance and long-term potentiation defects. We also identify distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses, associated with deficiencies in crucial presynaptic release regulators. WhileTRIO K1431Mhas impaired ability to promote GTP exchange on Rac1,+/K1431Mmice exhibit increased Rac1 activity, suggesting possible compensation by other GEFs. Our work reveals that discrete disease-associatedTriovariants yield overlapping but distinct NDD-associated phenotypes in mice and demonstrates, for the first time, an essential role for Trio in presynaptic glutamate release, underscoring the importance of studying the impact of variant heterozygosity in vivo.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Ishchenko,

Jeng,

Feng

et al. 2024

Preprint

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Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity

Zhang

Zablah

Zhang

et al. 2022

Front. Aging Neurosci.

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Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer’s disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear. In this study, we used local injections of AAV virus containing a dominant-negative (DN) Rac1 under the control of CaMKIIα promoter and found that the reduction of Rac1 hyperactivity in ventral hippocampal excitatory neurons improves social recognition memory in APP/PS1 mice. Expression of DN Rac1 also improves long-term potentiation, a key synaptic mechanism for memory formation. Our results suggest that overactivation of Rac1 in hippocampal excitatory neurons contributes to social memory deficits in APP/PS1 mice and that manipulating Rac1 activity may provide a potential therapeutic strategy to treat social deficits in AD.

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Activation of Rac1 Has an Opposing Effect on Induction and Maintenance of Long-Term Potentiation in Hippocampus by Acting on Different Kinases

Cited by 2 publications

References 19 publications

Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity

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