Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures

Abstract

There are no detailed descriptions of neuronal circuit active during frontal lobe motor seizures. Using activity reporter mice, local field potential recordings, tissue clearing, viral tracing, and super-resolution microscopy, we found neuronal activation after focal motor to bilateral tonic-clonic seizures in the striatum, globus pallidus externus, subthalamic nucleus, substantia nigra pars reticulata and neurons of the indirect pathway. Seizures preferentially activated dopamine D2 receptor-expressing neurons over D1 in the striatum, which have different projections. Furthermore, the D2 receptor agonist infused into the striatum exerted an anticonvulsant effect. Seizures activate structures via short and long latency loops, and anatomical connections of the seizure focus determine the seizure circuit. These studies, for the first time, show activation of neurons in the striatum, globus pallidus, subthalamic nucleus, and substantia nigra during frontal lobe motor seizures on the cellular level, revealing a complex neuronal activation circuit subject to modulation by the basal ganglia.

Connectivity and Neuronal Synchrony during Seizures

“…Thus, our findings support the connectivity hypothesis that excitatory anatomic connections of the seizure focus drive seizure spread. This hypothesis is not only limited to the hippocampal circuit as our previous work in frontal lobe spontaneous seizures also supports it (Brodovskaya et al, 2021). Interestingly, we revealed that the propagation pattern is preserved in the lamellar direction throughout the kindling process, while no rapid propagation pattern is observed or emerges in the septotemporal direction.…”

Anticonvulsant dopamine type 2 receptor agonist activates inhibitory parvalbumin interneurons

“…To determine whether systemic D2R agonist injection was anticonvulsant, we administered full selective D2R agonist sumanirole (5 mg/kg ip) or normosol as a control. Because sumanirole has a sustained effect for at least 2 h, 6 we had two injection cohorts. In the first cohort, we did three consecutive injections to determine the anticonvulsant effect.…”

“…TRAP2 mice were perfused with 4% paraformaldehyde, sliced on a cryostat at 40 µm, immunolabeled with rabbit anti-NeuN (1:500, #24307, Cell Signaling) and rabbit anti-PV (1:500, #ab11427; Abcam), and imaged on a confocal microscope at 10×/.45 numerical aperture (NA) or 20×/.95 NA as described previously. 6 We used ImageJ and Imaris Spots detection tools to count tdTomato-positive cells in D2R agonist-injected versus noninjected mice. We subtracted background and adjusted the threshold to count cells.…”

“…1,2 We previously found that D2R agonist injected through a bilateral cannula directly into the striatum stopped frontal lobe seizures for 2.5 h following the injection. 6 Here, we wanted to determine whether systemic injection would also be anticonvulsant. Also, the mechanism behind dopamine receptor modulation of seizures is not fully understood.…”

TRAPing Seizures in the Striatum

“…Stephen King opined, in The Colorado Kid that , “sooner or later, everything old is new again.” It is one of the delights of science that we can make “old” targets new again, with new approaches that provide greater resolution and heightened precision. In their recent manuscript, Brodovskaya and colleagues 1 examined an “old” set of structures—the basal ganglia, using new approaches to map, with cell-type specific resolution, the pathways engaged by seizures originating in the frontal cortex.…”