Abstracts

Rationale: Modulation of activity in the basal ganglia can restrain seizures in several rodent models of epilepsy. The majority of research has focused on the substantia nigra pars reticulata (SNpr), a main output nucleus of the basal ganglia (BG), and its projections to the superior colliculus. Less, however, is known about the role of upstream basal ganglia nuclei, such as the striatum, in the control of seizures. Prior studies have been limited in their ability to directly target and manipulate opposing striatal output pathways. In the present work, we utilize a cre-dependent optogenetic approach to dissect the roles of the anatomically and functionally distinct direct and indirect BG pathways in seizure control. We hypothesized that activation of striatal direct pathway neurons (which inhibit the SNpr) or inactivation of striatal indirect pathway neurons (which indirectly excite the SNpr) would suppress seizure activity. These hypotheses are based on the well-established anticonvulsant effects achieved by pharmacological inhibition of the SNpr. Methods: For this study we used dopamine receptor D1- and D2-cre transgenic rats on a Long-Evans background from NIDA. Adult male rats were microinjected with cre-dependent virus encoding optogenetic constructs and fixed with fiber optics into the rostral part of the dorsal striatum. Stimulating/recording electrodes were placed in the left basolateral amygdala. One week after surgery animals began the kindling paradigm which consisted of daily electrical stimulations. After five seizures displaying rearing and loss of balance (corresponding to a score of 5 on the Racine Scale), animals underwent optogenetic testing. We tested animals for seizure threshold and seizure manifestation (electrographic and behavioral) with and without light delivery. Additionally, since unilateral BG manipulations typically elicit a contralateral movement bias, we tested evoked rotational responses with unilateral optogenetic manipulations. Results: Activation of direct pathway striatal projection neurons (SPNs) increased seizure threshold (p=.06) and reduced seizure duration (p=.06) but did not alter severity of behavioral seizure manifestations. Unilateral activation of direct pathway (n=6) resulted in a contraversive movement bias (p=.04), as expected. Silencing indirect pathway SPNs in rats (n=4) suppressed behavioral manifestations (p=.03) and electrographic discharge (p=.04) without altering seizure threshold; animals displayed a contraversive movement bias in response to unilateral administration of light (n=8, p=.08), as expected. Conclusions: Both direct and indirect pathway manipulations reduced parameters of seizure activity. However, there was a dissociation in impact on behavioral seizure manifestations. These data suggest that the striatum, as an upstream regulator of SNpr activity, modulates seizure behavior in limbic epilepsy. However, the role of other nodes of the direct and indirect pathway circuitry remain to be explored. Funding: NIH R01 NS097762 to PAF