PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice

Marsillo, Alexandra; David, Lovena; Gerges, Bishoy; Kerr, Daniel J.; Sadek, Rodina; Lasiychuk, Vitaliy; Salame, David; Soliman, Youstina; Menkes, Silvia; Chatterjee, Aheli; Mancuso, Andrew

doi:10.1016/j.bbadis.2020.166048

Cited by 12 publications

(7 citation statements)

References 53 publications

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“…An early study on cortical synaptoneurosomes found that basal PKC activity was not different between wild type and fmr1 KO mice 43 . A more recent study, however, found that PKCε expression was significant lower in the hippocampus of fmr1 KO mice 44 . While not a canonical PKC isoform, in that it is not sensitive to intracellular Ca 2+ , PKCε is abundant in the nervous system and activated by G-protein coupled receptors 45 .…”

Section: Potential Mechanism For the Hyperpolarized Activation Of A-tmentioning

confidence: 83%

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

Ordemann¹,

Apgar²,

Chitwood³

et al. 2021

Preprint

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Section: Potential Mechanism For the Hyperpolarized Activation Of A-tmentioning

confidence: 83%

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

Ordemann¹,

Apgar²,

Chitwood³

et al. 2021

Preprint

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“…A study on cortical synaptoneurosomes found that basal PKC activity was not different between wild-type and fmr1 KO mice (Weiler et al, 2004). A more recent study, however, found that PKC« expression was lower in the hippocampus of fmr1 KO mice (Marsillo et al, 2021). PKC« is abundant in the nervous system and activated by G proteincoupled receptors (Akita, 2002).…”

Section: Dendritic Nonlinear Events In Fmr1 Ko Ca1 Neuronsmentioning

confidence: 97%

Altered A-Type Potassium Channel Function Impairs Dendritic Spike Initiation and Temporoammonic Long-Term Potentiation in Fragile X Syndrome

et al. 2021

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Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism spectrum disorder. Area CA1 of the hippocampus receives current information about the external world from the entorhinal cortex via the temporoammonic (TA) pathway. Given its role in learning and memory, it is surprising that little is known about TA long-term potentiation (TA-LTP) in FXS. We found that TA-LTP was impaired in male fmr1 KO mice. Although there were no significant differences in basal synaptic transmission, synaptically evoked dendritic calcium signals were smaller in KO neurons. Using dendritic recording, we found no difference in complex spikes or pharmacologically isolated Ca 21 spikes; however, the threshold for fast, Na 1 -dependent dendritic spikes was depolarized in fmr1 KO mice. Cell-attached patch-clamp recordings found no difference in Na 1 channels between wild-type and fmr1 KO CA1 dendrites. Dendritic spike threshold and TA-LTP were restored by blocking A-type K 1 channels with either 150 mM Ba 21 or the more specific toxin AmmTx3. The impairment of TA-LTP shown here, coupled with previously described enhanced Schaffer collateral LTP, may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K 1 channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS.

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“…One alternative possibility is that loss of FMRP affects intracellular second-messenger signaling pathways that may regulate Kv7 activity (Haick et al 2017). For example, activation of PKC suppresses Kv7 function (Delmas & Brown 2005, Haick et al 2017 and PKCε expression was found to be reduced in hippocampus of Fmr1 KO mice (Marsillo et al 2021), supporting a possibility that the increased Kv7 function in KO MCs may be associated with abnormal PKC signaling. However, further studies will be needed to elucidate the precise mechanism responsible for the increased Kv7 function in Fmr1 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Circuit-based intervention corrects excessive dentate gyrus output in the Fragile X mouse model

Deng,

Kumar,

Cavalli

et al. 2023

Preprint

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Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell hypo-excitability is caused by increased Kv7 function inFmr1KO mice. By reducing the excitatory drive onto local hilar interneurons, hypo-excitability of mossy cells results in increased excitation/inhibition ratio in granule cells and thus paradoxically leads to excessive dentate output. Circuit-wide inhibition of Kv7 channels inFmr1KO mice increases inhibitory drive onto granule cells and normalizes the dentate output in response to physiologically relevant theta-gamma coupling stimulation. Our study suggests that circuit-based interventions may provide a promising strategy in this disorder to bypass irreconcilable excitability defects in different cell types and restore their pathophysiological consequences at the circuit level.

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PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice

Cited by 12 publications

References 53 publications

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

Altered A-Type Potassium Channel Function Impairs Dendritic Spike Initiation and Temporoammonic Long-Term Potentiation in Fragile X Syndrome

Circuit-based intervention corrects excessive dentate gyrus output in the Fragile X mouse model

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