Plain wording

In juvenile Kcnc1-A421V mice, less Kv3.1 reaches the surface of parvalbumin interneurons and more of it stays inside the cell.

slug a421v-kv31-membrane-trafficking-impairedrole empiricalpanel fig3H, fig3I

Every Kcnc1-A421V mouse dies before 122 days of age, while wild-type littermates live on.

slug a421v-mice-die-before-122drole empiricalpanel fig1

Young adult Kcnc1-A421V mice are slower to learn the Barnes maze and alternate less in the Y-maze, but retain what they learned.

slug a421v-spatial-learning-working-memory-impairedrole empiricalpanel fig2B, fig2C, fig2D

Kcnc1-A421V mice weigh less and have smaller brains than littermates, yet reach the usual early developmental milestones on time.

slug a421v-weight-reduced-milestones-normalrole empiricalpanel fig1—figure supplement 2B, 2C, 2D, 2E

Inhibition in Kcnc1-A421V mice is already impaired in juveniles, so the deficit is fixed from the start rather than worsening with age.

slug alt-inhibitory-dysfunction-present-juvenilerole hypothesis

Excitatory neurons in adult Kcnc1-A421V mice fire like wild-type ones, apart from needing slightly less current to start firing.

slug excitatory-neurons-unaffected-adultrole controlpanel fig5—figure supplement 1D, Table 2 (layer IV exc. cells)

Excitatory neurons in juvenile Kcnc1-A421V mice show normal synaptic transmission and normal excitability.

slug excitatory-neurons-unaffected-juvenilerole controlpanel fig5B, fig5C, fig5D, fig5E, fig5F, fig5G, fig5K, Table 1 (la…

The A421V variant weakens Kv3.1 by keeping the channel from reaching the cell surface, not by changing how the channels that arrive work.

slug hypothesis-a421v-causes-kv31-lofrole hypothesispanel hypothesis

Losing Kv3.1 in parvalbumin interneurons is by itself enough to produce the seizures, sudden death and cognitive deficits of KCNC1 disease.

slug hypothesis-pv-dysfunction-drives-encephalopathyrole hypothesispanel hypothesis

Kv3.1 loss impairs fast-spiking parvalbumin interneurons and spares excitatory neurons, hitting hardest where Kv3.2 cannot compensate.

slug hypothesis-pv-in-selective-vulnerabilityrole hypothesispanel hypothesis

Awake Kcnc1-A421V mice show bursts of synchronised cortical activity accompanied by brief twitches, and wild-type mice never do.

slug in-vivo-hypersynchronous-discharges-mutant-onlyrole empiricalpanel fig8B, fig8C, fig8D

During quiet rest, excitatory cells in Kcnc1-A421V mice are active more often while parvalbumin cells respond more weakly.

slug in-vivo-pv-minus-transient-frequency-increasedrole empiricalpanel fig8G, fig8H, fig8I, fig8J

Inhibitory transmission is normal in juvenile Kcnc1-A421V mice and impaired by young adulthood, so the deficit emerges with age.

slug inhibitory-dysfunction-progresses-to-adulthoodrole synthesispanel figs 2-4

The paper's main phenotype claims rest on the knock-in mouse colony and bench recordings, and cannot be checked from deposited data alone.

slug kcnc1-wet-lab-primary-claimsrole methodologicalpanel all figures (assessment)

Layer V parvalbumin interneurons in juvenile mutants are only mildly impaired, firing less at the strongest current injections.

slug layer-v-pv-ins-subtle-impairmentrole empiricalpanel fig4—figure supplement 2

Kcnc1-A421V mice should be slower to learn the Barnes maze and show weaker Y-maze working memory, with no locomotor explanation.

slug prediction-cognitive-deficitsrole predictionpanel prediction

Excitatory neurons should be unaffected in Kcnc1-A421V mice at both juvenile and adult ages, since they barely rely on Kv3.1.

slug prediction-excitatory-neurons-sparedrole predictionpanel prediction

Deficits should be largest in parvalbumin cells that depend most on Kv3.1 and milder where Kv3.2 can take over.

slug prediction-impairment-grades-with-kv31-dependencerole predictionpanel prediction

Mutant parvalbumin interneurons should hold less Kv3.1 at the membrane and more inside the cell, while the remaining channels open normally.

slug prediction-kv31-surface-expression-reducedrole predictionpanel prediction

Awake Kcnc1-A421V mice should show synchronised cortical discharges and more active excitatory cells during quiet rest.

slug prediction-network-hyperexcitability-in-vivorole predictionpanel prediction

Inhibitory synapses made by parvalbumin interneurons should work normally in juveniles and release transmitter differently in young adults.

slug prediction-progressive-synaptic-failurerole predictionpanel prediction

Parvalbumin interneurons in mutants should fire more slowly with broader, less sharply repolarising spikes, already in juveniles.

slug prediction-pv-in-firing-impairedrole predictionpanel prediction

Parvalbumin interneurons carrying one copy of the variant should lose voltage-gated potassium current, and lose more than half of it.

slug prediction-pv-in-k-current-reducedrole predictionpanel prediction

Kcnc1-A421V mice should have spontaneous convulsive seizures on video-EEG and die suddenly after tonic-clonic seizures.

slug prediction-seizures-and-sudeprole predictionpanel prediction

Spikes in mutant parvalbumin interneurons repolarise more slowly and last longer, at both juvenile and adult ages.

slug pv-in-ap-waveform-altered-downstroke-apd50role empiricalpanel fig4E, fig4J, Table 1, Table 2

In adult mutants, inhibitory signals from parvalbumin interneurons onto excitatory cells are larger but weaken faster during repeated firing.

slug pv-in-inhibitory-synapse-altered-adultrole empiricalpanel fig7F, fig7G, fig7H, fig7I

In juvenile mutants, inhibitory transmission from parvalbumin interneurons onto excitatory cells is no different from wild-type.

slug pv-in-inhibitory-synapse-intact-juvenilerole empiricalpanel fig6F, fig6G, fig6H, fig6I, fig6J, fig6K, fig6L

Parvalbumin interneurons from Kcnc1-A421V mice cannot sustain the high firing rates that wild-type cells reach.

slug pv-ins-impaired-maximal-firingrole empiricalpanel fig2, fig3

Parvalbumin interneurons in Kcnc1-A421V mice carry less voltage-gated potassium current than wild-type cells.

slug pv-ins-reduced-k-current-densityrole empiricalpanel fig2

Parvalbumin neurons of the reticular thalamic nucleus in juvenile mutants fire fewer rebound spikes and repolarise more slowly.

slug rtn-neurons-impaired-excitabilityrole empiricalpanel fig4—figure supplement 3

All claims come from one heterozygous Kcnc1-A421V knock-in mouse line, studied in somatosensory cortex and thalamus at set ages.

slug scope-a421v-knockin-mouserole scopepanel scope

Most Kcnc1-A421V mice have spontaneous convulsive seizures on video-EEG and some die suddenly after one, while wild-types have none.

slug spontaneous-seizures-and-sudep-kcnc1role empiricalpanel fig9A, fig9B, fig9C