Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia

Miyamae, Takeaki; Hashimoto, Takako; Abraham, Monica; Kawabata, Rika; Koshikizawa, Sho; Bian, Yufan; Nishihata, Yosuke; Kikuchi, Mitsuru; Ermentrout, G. Bard; Lewis, David A.; González‐Burgos, Guillermo

doi:10.1016/j.nbd.2021.105382

Cited by 11 publications

(7 citation statements)

References 83 publications

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“…Interestingly, three scaffolds near the chromosomal end ( i.e., at the beginning of the p-arm, as well as at the end of the q-arm in the genomic coordinate of the ZAL2 chromosome), exhibited both decreased F ST values and a reduced rate of fixed genetic differences (Df). One possible explanation for these findings is that these regions represent a younger evolutionary stratum ( 59–61 ). Another possibility is that the within-ZAL2 nucleotide diversity is increased and that this inflated diversity within the sampled population reduced the F ST estimate.…”

Section: Resultsmentioning

confidence: 99%

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Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

Jeong¹,

Baran

Sun

et al. 2022

Preprint

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In the white throated sparrow (Z. albicollis), two alternative morphs differing in both plumage and behavior segregate with a large rearrangement on the second largest chromosome. As with sex chromosomes, the rearranged version of chromosome 2 (known as ZAL2m), is maintained in a near-constant state of heterozygosity, offering a unique opportunity to investigate how both degenerative and selective processes act during the early evolutionary stages of 'supergenes.' Here we generated, synthesized, and analyzed extensive genomic and transcriptomic data to better understand, at a finer resolution than has previously been possible, the evolutionary forces shaping the evolution of both ZAL2m and the standard version of the chromosome, ZAL2. First, we found that features of ZAL2m are consistent with substantially reduced recombination and low levels of degeneration. Second, we found evidence of selective sweeps having taken place on both ZAL2 and ZAL2m chromosomes after the rearrangement event. Third, we showed that positive selection is associated with allelic bias in gene expression in the brain, suggesting that antagonistic selection has operated on gene regulation. Finally, we discovered a 15-gene region exhibiting two long-range haplotypes inside the rearrangement on ZAL2m. Remarkably, these two haplotypes appear to have been maintained by balancing selection, retaining genetic diversity within the non-recombining autosomal supergene. Together, these analyses illuminate the evolution of a young chromosomal polymorphism, revealing that complex selective processes act concurrently with genetic degeneration to drive the evolution of supergenes.

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Section: Resultsmentioning

confidence: 99%

“…One possible explanation for these findings is that these regions represent a younger evolutionary stratum (59)(60)(61). Another possibility is that the within-ZAL2 nucleotide diversity is increased and that this inflated diversity within the sampled population reduced the FST estimate.…”

Section: Candidates For Positive Selection In Zal2 and Zal2 Mmentioning

confidence: 99%

Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

Jeong¹,

Baran

Sun

et al. 2022

Preprint

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“…Candidate genes belonging to these pathways were selected based on their involvement in gamma oscillations and FSI functionality as potential causes of early functional impairment during amyloid pathology progression. Kcnc1 [45–47] , Kcns3 [48,49] , Scn1a [50,51] , Erbb4 [52–55] , GABRA1 [56,57] and Syt2 [58–61] were upregulated in the App NL-G-F group at P60 (Fig 3.C; Supp table 1).…”

Section: Resultsmentioning

confidence: 99%

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression

Pizzirusso,

Preka,

Goikolea

et al. 2024

Preprint

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Alzheimer’s disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer’s disease onset and progression. Characterizing the initial phase of Alzheimer’s disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used theAppNL-G-Fknock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer’s disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network’s functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimer’s disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

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“…Additionally, there was a trend for the gene KCNS3 to be more highly expressed in both Hyp (unadjusted p=0.0511) and AMV (unadjusted p = 0.1567). This gene encodes a voltage-gated channel subunit that in humans and mice is specific to fast-spiking parvalbumin (inhibitory) neurons ( Georgiev et al, 2014 ; Miyamae et al, 2021 ). Although no genes were significantly differentially expressed at the genome-wide level, our current findings provide potentially interesting candidates to explore further in the context of behavioral differences between the morphs.…”

Section: Resultsmentioning

confidence: 99%

Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

Jeong

Baran

Sun

et al. 2022

eLife

View full text Add to dashboard Cite

In white-throated sparrows, two alternative morphs differing in plumage and behavior segregate with a large chromosomal rearrangement. As with sex chromosomes such as the mammalian Y, the rearranged version of chromosome two (ZAL2m) is in a near-constant state of heterozygosity, offering opportunities to investigate both degenerative and selective processes during the early evolutionary stages of ‘supergenes.’ Here, we generated, synthesized, and analyzed extensive genome-scale data to better understand the forces shaping the evolution of the ZAL2 and ZAL2m chromosomes in this species. We found that features of ZAL2m are consistent with substantially reduced recombination and low levels of degeneration. We also found evidence that selective sweeps took place both on ZAL2m and its standard counterpart, ZAL2, after the rearrangement event. Signatures of positive selection were associated with allelic bias in gene expression, suggesting that antagonistic selection has operated on gene regulation. Finally, we discovered a region exhibiting long-range haplotypes inside the rearrangement on ZAL2m. These haplotypes appear to have been maintained by balancing selection, retaining genetic diversity within the supergene. Together, our analyses illuminate mechanisms contributing to the evolution of a young chromosomal polymorphism, revealing complex selective processes acting concurrently with genetic degeneration to drive the evolution of supergenes.

show abstract

Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia

Cited by 11 publications

References 83 publications

Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression

Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

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