APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

Chen, Ming; Wang, Jinzhao; Jiang, Jinxiang; Zheng, Xingzhi; Justice, Nicholas J.; Wang, Kun; Ran, Xiangqian; Li, Yang; Huo, Qingwei; Zhang, Jiajia; Li, Hongmei; Lu, Nannan; Wang, Ying; Zheng, Hui; Long, Cheng

doi:10.7554/elife.20142

Cited by 85 publications

(75 citation statements)

References 58 publications

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“…In extracellular hippocampal slice recordings from KCC2 +/− mice, spontaneous events displayed both increased amplitude and frequency, highlighting a potential difference in the effects of lower KCC2 expression between brain regions [Zhu et al, ]. However, we did not observe any change in mIPSC amplitude in the mPFC, despite the known action of KCC2 on chloride channels and expected effects on GABA signaling, and this effect is consistent with another study that recorded currents in the hippocampus, in which KCC2 protein expression was decreased by about 50%, although this was due to the knockout of amyloid precursor protein [Chen et al, ]. This could suggest that the observed effects on mEPSCs reflect the summed impact of KCC2 loss across circuits, rather than simply reflecting effects within the dmPFC pyramidal neurons themselves.…”

Section: Discussionsupporting

confidence: 90%

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

et al. 2019

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The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2 +/− mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2 +/− mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2 +/− mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes.Lay Summary: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors.

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Section: Discussionsupporting

confidence: 90%

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

et al. 2019

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“…For instance, we found that the level of GABA receptor subunit alpha 1 (GABARα1) was diminished in the absence of APP and in NPAS4-deficient neurons. This is in agreement with recent study showing that GABARα1 is particularly decrease in hippocampus of APP-/- mice (Chen et al 2017) correlating with a decrease in IPSC amplitude. But on the other hand, it suggests that increases in GABA release in APP-deficient models may not result in a net increase of inhibitory transmission, or at least there is a complex modulation of neuronal response to GABA.…”

Section: Discussionsupporting

confidence: 94%

“…APP was also described to play an important role in GABAergic inhibitory neurotransmission. APP deficiency reduces paired pulse depression (PPD) in mice (Seabrook et al, 1999) and affects GABA receptors expressions (Fitzjohn et al, 2000; Chen et al, 2017), while APP overexpression induces hyperexcitability due to GABAergic neurotransmission failure (Born et al, 2014). Recently, APP was associated with the GABA excitatory/inhibitory shift occurring in embryonic neurons (Doshina et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Protein (APP) controls excitatory/inhibitory synaptic inputs by regulating the transcriptional activator Neuronal PAS Domain Protein 4 (NPAS4)

Opsomer

Contino

Perrin

et al. 2018

Preprint

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33Sequential proteolysis of the amyloid precursor protein (APP) and amyloid-β peptide (Aβ) release 34is an upstream event in Alzheimer's disease (AD) pathogenesis. The function of APP in neuronal 35 physiology is still, however, poorly understood. Along with its paralog APP-like Proteins 1 and 2 36 (APLP1-2), APP is involved in neurite formation and synaptic function by mechanisms that are 37 not elucidated. APP is a single-pass transmembrane protein expressed at high levels in the brain 38 that resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies 39 on cell interaction processes and/or activation of intracellular pathways of signal transduction. 40Along this line, the APP intracellular domain (AICD) was reported to act as a transcriptional factor 41 for targeted gene activation that mediates physiological APP functions. Here, we used an unbiased 42 transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent 43 embryonic cortex and upon maturation of primary cortical neurons. The transcriptome analysis did 44 not detect any significant differences in expression of previously proposed AICD target genes. The 45 overall transcriptional changes were subtle, but we found that genes clustered in neuronal-activity 46 dependent pathways are dysregulated in the absence of APP. Among these genes, we found the 47 activity-dependent Neuronal PAS domain protein 4 (NPAS4) Immediate Early Gene to be 48 downregulated in the absence of APP. Down-regulation of NPAS4 in APP knock-out (KO) neurons 49is not related to AICD but to the APP ectodomain. We studied the effect of APP deficiency on 50GABAergic and glutamatergic transmission, and found an increased production of the inhibitory 51 neurotransmitter GABA in APP KO neurons, along with a reduced expression of the GABA (A) 52 receptors alpha1, suggesting an impaired GABAergic neurotransmission in the absence of APP. 53 CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Altogether, our 54 results point out a new role for APP in the regulation of excitatory/inhibitory neurotransmission 55 through the regulation of the activity-dependent NPAS4 gene. 56 4 excitation onto the same neurons (Spiegel et al., 2014). NPAS4 is therefore a key player in the 96 maintenance of excitatory/inhibitory balance in neuronal network. 97The precise mechanisms underlying APP synaptic functions are still elusive. One could suspect 98 APP to regulate the expression of genes involved in synaptic activity, or to shape the structure of 99 the synapse. APP was shown to control gene expression through its intracellular domain called 100AICD. An increasing list of AICD candidate genes has emerged from various models (reviewed in 101Pardossi-Piquard and Checler, 2012). Some of these candidate genes failed to be confirmed by 102 transcription analysis in APP-deficient cell lines (Hebert et al., 2006; Waldron et al., 2008), and 103 APP was also reported to regulate gene transcription independently of AICD...

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“…The differences in mRNA and protein expression suggest that NKCC1 and KCC2 are post-translationally modified. 21,22 KCC2 also plays a role in synapse stabilisation through cytoskeletal interactions that is independent of its chloride transporter function, 23,24 providing another possible mechanism by which a testosterone-mediated delay of KCC2 expression 4 leads to slower maturation of neural circuitry in males. Expression of KCC2 and NKCC1 is critical to early brain development and exhibits marked sex-specific postnatal developmental expression.…”

Section: Discussionmentioning

confidence: 99%

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Russell

Chinn

Maharjan

et al. 2019

British Journal of Anaesthesia

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Background: The factors determining peak susceptibility of the developing brain to anaesthetics are unclear. It is unknown why postnatal day 7 (P7) male rats are more vulnerable to anaesthesia-induced memory deficits than littermate females. Given the precocious development of certain regions in the female brain during the neonatal critical period, we hypothesised that females are susceptible to anaesthetic brain injury at an earlier time point than previously tested. Methods: Female rats were exposed to isoflurane (Iso) 1 minimum alveolar concentration or sham anaesthesia at P4 or P7. Starting at P35, rats underwent a series of behavioural tasks to test their spatial and recognition memory. Cell death immediately after anaesthesia was quantified by Fluoro-Jade C staining in select brain regions, and developmental expression of the chloride transporters KCC2 and NKCC1 was analysed by immunoblotting in male and female rats at P4 and P7. Results: Female rats exposed to Iso at P4 displayed impaired spatial, object-place, -context, and social recognition memory, and increased cell death in the hippocampus and laterodorsal thalamus. Female rats exposed at P7 exhibited only decreased performance in object-context compared with control. The ratio of NKCC1/KCC2 expression in cerebral cortex was higher in P4 females than in P7 females, and similar to that in P7 males. Conclusions: Female rats exposed to Iso at P4 are sensitive to anaesthetic injury historically observed in P7 males. This is consistent with a comparably immature developmental state in P4 females and P7 males. The window of anaesthetic vulnerability correlates with sex-specific cortical expression of chloride transporters NKCC1 and KCC2. These findings suggest that both sex and developmental age play important roles in determining the outcome after early anaesthesia exposure.

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APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

Cited by 85 publications

References 58 publications

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

Amyloid Precursor Protein (APP) controls excitatory/inhibitory synaptic inputs by regulating the transcriptional activator Neuronal PAS Domain Protein 4 (NPAS4)

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

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