Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.

Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome.

PURPOSE: Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV 1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced γ-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS. METHODS: We have studied heterozygous NaV 1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures. KEY FINDINGS: In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase. SIGNIFICANCE: We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches.

Effective Letermovir Prophylaxis of CMV infection post allogeneic hematopoietic cell transplantation: Results from the French temporary authorization of use compassionate program.

We report the results of the French Temporary Authorization of Use (ATU) compassionate program of letermovir for primary prophylaxis conducted in 21 transplant centers. Patients were CMV seropositive allogeneic hematopoietic cell transplantation recipients and at high risk for CMV infection. Primary prophylaxis was defined as initiation of letermovir between day 0 and day +28 post-transplant. Between November 2017 and January 2019, 96 patients with a median age of 56 years received letermovir and follow-up data were available for 78 patients. The median time from transplant to letermovir initiation was 4 days, and the median duration of exposure to letermovir was 78 days, with 57 patients still on treatment at the cutoff date. Letermovir was temporarily discontinued in 4 patients (5.1%) and stopped in 39 patients (50.0%), in most cases due to planned end of treatment (n = 16, 20.5%). Fifteen patients (19.2%) each presented one positive CMV PCR, in median 13 days after letermovir initiation. Clinically significant CMV infection was reported in 5 patients (6.4%). No CMV disease was reported. At least one adverse drug reaction was reported for 12 patients (15.4%). In this early access program, letermovir was effective with comparable results of the phase 3 study with a low rate of clinically significant CMV infection, including in patients who were at high-risk for CMV infection.