Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice

Abstract

Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE. Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.

Targeted hippocampal GABA neuron ablation by Stable Substance P–saporin causes hippocampal sclerosis and chronic epilepsy in rats

“…This finding suggests that a preexisting focal GABAergic defect may be sufficient to initiate a clinically subtle focal excitotoxic insult that replicates the defining features of cryptogenic TLE-HS+ [1][2][3][4] and may be the rat analog of prolonged febrile seizures in children. [5][6][7] Earlier attempts to demonstrate the epileptogenic potential of selective hippocampal GABAergic dysfunction 12,15-17 may have been unsuccessful because the extent of GABA neuron loss was too spatially limited, 12 or because the experimental designs did not sufficiently involve the dentate gyrus, [15][16][17] which plays a central role in producing hippocampal sclerosis and chronic granule cell-onset epilepsy. [8][9][10][11] Although it is not currently possible to identify the ultimate neuronal source of any spontaneous seizure, we use the term granule cell-onset seizures to describe behavioral seizures in which the first behavioral sign was reliably preceded by high-amplitude granule cell layer activity, as previously described.…”

Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

“… 28 Indeed, we found that ECB device-mediated BDNF supplementation can lead to a robust increase in the number of parvalbumin-positive cells in the hippocampus, returning them to nearly control levels. Parvalbumin interneurons are known to degenerate in both patients 29 and animal models of temporal lobe epilepsy (TLE) 30 , 31 , 32 , 33 recently provided experimental evidence that selective, permanent inhibition of parvalbumin interneurons reduce perisomatic feed-forward inhibition in vivo , resulting in a decrease in seizure threshold and the development of spontaneous seizures (i.e., epilepsy). Based on our data, it is intriguing to hypothesize that ECB device-mediated BDNF supplementation can activate neurogenesis to produce (among others) new parvalbumin interneurons that contribute to decreased seizure frequency.…”

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

“…Fast-spiking interneurons are essential for proper network oscillations and disrupting the function of PV+INTs can generate spontaneous recurrent seizures (Drexel et al, 2017;Panthi and Leitch, 2019). Recent transcriptomics suggests that there are several genomically distinct subpopulations of PV+INTs (Hodge et al, 2019;Gouwens et al, 2020), some of which may correspond to unique PV+INT subtypes that have remained largely understudied relative to the canonical FS subtypes listed above.…”

“…PV-containing inhibitory interneurons (PV+INTs) are often classified as ‘fast-spiking’ cells due to their ability to sustain high-frequency discharges of action potentials with minimal spike-frequency adaptation/accommodation ( Pelkey et al, 2017 ). Fast-spiking interneurons are essential for proper network oscillations and disrupting the function of PV+INTs can generate spontaneous recurrent seizures ( Drexel et al, 2017 ; Panthi and Leitch, 2019 ). Recent transcriptomics suggests that there are several genomically distinct subpopulations of PV+INTs ( Hodge et al, 2019 ; Gouwens et al, 2020 ), some of which may correspond to unique PV+INT subtypes that have remained largely understudied relative to the canonical FS subtypes listed above.…”