Knierim E, Vogt J, Kintscher M, Ponomarenko A, Baumgart J, Beed P, Korotkova T, Trimbuch T, Panzer A, Steinlein OK, Stephani U, Escayg A, Koko M, Liu Y, Lerche H, Schmitz D, Nitsch R, Schuelke M (in press). Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype. Cereb Cortex. https://doi.org/10.1093/cercor/bhad051
The Phospholipid Phosphatase Related 4 gene (PLPPR4, *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM_014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM_006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM_014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE.
The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4−/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans.
Chalas N, Daube C, Kluger DS, Abbasi O, Nitsch R, Gross J (in press). Speech onsets and sustained speech contribute differentially to delta and theta speech tracking in auditory cortex. Cereb Cortex
When we attentively listen to an individual's speech, our brain activity dynamically aligns to the incoming acoustic input at multiple timescales. Although this systematic alignment between ongoing brain activity and speech in auditory brain areas is well established, the acoustic events that drive this phase-locking are not fully understood. Here, we use magnetoencephalographic recordings of 24 human participants (12 females) while they were listening to a 1 h story. We show that whereas speech-brain coupling is associated with sustained acoustic fluctuations in the speech envelope in the theta-frequency range (4-7 Hz), speech tracking in the low-frequency delta (below 1 Hz) was strongest around onsets of speech, like the beginning of a sentence. Crucially, delta tracking in bilateral auditory areas was not sustained after onsets, proposing a delta tracking during continuous speech perception that is driven by speech onsets. We conclude that both onsets and sustained components of speech contribute differentially to speech tracking in delta- and theta-frequency bands, orchestrating sampling of continuous speech. Thus, our results suggest a temporal dissociation of acoustically driven oscillatory activity in auditory areas during speech tracking, providing valuable implications for orchestration of speech tracking at multiple time scales.