Descending projections from the substantia nigra pars reticulata differentially control seizures

Abstract

Three decades of studies have shown that inhibition of thesubstantia nigra pars reticulata(SNpr) attenuates seizures, yet the circuits mediating this effect remain obscure. SNpr projects to the deep and intermediate layers of the superior colliculus (DLSC) and the pedunculopontine nucleus (PPN), but the contributions of these projections are unknown. To address this gap, we optogenetically silenced cell bodies within SNpr, nigrotectal terminals within DLSC, and nigrotegmental terminals within PPN. Inhibition of cell bodies in SNpr suppressed generalized seizures evoked by pentylenetetrazole (PTZ), partial seizures evoked from the forebrain, absence seizures evoked by gamma-butyrolactone (GBL), and audiogenic seizures in genetically epilepsy-prone rats. Strikingly, these effects were fully recapitulated by silencing nigrotectal projections. By contrast, silencing nigrotegmental terminals reduced only absence seizures and exacerbated seizures evoked by PTZ. These data underscore the broad-spectrum anticonvulsant efficacy of this circuit, and demonstrate that specific efferent projection pathways differentially control different seizure types.

Divergent Effects of Systemic and Intracollicular CB Receptor Activation Against Forebrain and Hindbrain-Evoked Seizures in Rats

“…We had hypothesized that the DLSC might be a critical site of action for CB-mediated anti-convulsant effects. This was based on: (1) the well-established role the DLSC plays in audiogenic seizures, and in particular, in the wild-running phase which is typical of the GEPR-3 strain (Merrill et al, 2005 ); (2) volumetric changes in the SC in GEPR-3 rats (Lee et al, 2018 ); (3) the interconnections between the substantia nigra pars reticulata and the DLSC and the density of CB1 receptors in the SNpr (Herkenham et al, 1991 ; Matsuda et al, 1992 ; Glass et al, 1997 ; Tsou et al, 1998 ); (4) the presence of CB1 immunopositive axons in the DLSC (Tsou et al, 1998 ; Sañudo-Peña et al, 2000 ); (5) the anticonvulsant effects of activation of the DLSC (Soper et al, 2016 ); and (6) the anticonvulsant effects of disinhibition of the SC through inhibition of nigrotectal projections (Wicker et al, 2019 ). Consistent with our hypothesis, we found that the focal application of CP to the DLSC suppressed both AGSs and AT-evoked seizures.…”

“…These drug doses were chosen based on published reports (Sañudo-Peña et al, 2000 ; Citraro et al, 2013 ; Florek-Luszczki et al, 2014a ). Drug microinfusions were performed essentially as we have previously described (Wicker and Forcelli, 2016 ; Wicker et al, 2019 ). In brief, rats were gently restrained and a 28-gauge internal cannula was inserted.…”

“…In rats and mice, bilateral lesions of the superior colliculus, microinjection of GABA antagonist (Depaulis et al, 1990 ), N -methyl-D-aspartate (NMDA) antagonist (Faingold and Casebeer, 1999a ; Raisinghani and Faingold, 2003 ) or alpha1-noradrenergic agonist (Faingold and Casebeer, 1999a ) markedly attenuated AGS severity (Merrill et al, 2003 ). In a different approach, optogenetic activation of DLSC also attenuates seizures in Genetically Epilepsy-Prone Rat (GEPR) 3 substrain (Soper et al, 2016 ; Wicker et al, 2019 ). Activation of the DLSC also potently suppresses seizures in other models of epilepsy, including the maximal electroshock model (Redgrave et al, 1992 ; Gale et al, 1993 ), evoked and genetic absence seizure models (Nail-Boucherie et al, 2002 , 2005 ; Soper et al, 2016 ); the Area Tempestas (AT) model of forebrain seizures (Soper et al, 2016 ), and the pentylenetetrazole model of generalized seizures (Weng and Rosenberg, 1992 ; Soper et al, 2016 ).…”

“…Somewhat paradoxically, in the context of seizure suppression, the CB1 receptor co-localizes with GABA neurons in many brain regions it has been suggested that the primary cell type that expresses CB1 receptor is inhibitory (Katona et al, 1999 , 2001 ). This is of particular interest in the context of the DLSC, as disinhibition of the DLSC by silencing GABAergic inputs from the substantia nigra pars reticulata (SNpr) is also potently anticonvulsant (Wicker et al, 2019 ). Both the DLSC and the SNpr express CB1 receptors, with the SNpr displaying some of the highest receptor density in the brain (Herkenham et al, 1991 ).…”

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

“…Unilateral optogenetic stimulation also suppressed seizures but was accompanied by behavioral adverse effects such as contraversive posturing, freezing, or startle response in some of the rats. Optogenetic inhibition of SNr cells suppressed generalized seizures evoked by PTZ, focal bicuculline-induced seizures evoked from the anterior piriform cortex, absence seizures evoked by gamma-butyrolactone, and audiogenic seizures in genetically epilepsy-prone rats [248]. Noteworthy, these effects were reproduced by silencing nigrotectal projections, while silencing nigrotegmental terminals reduced only absence seizures and exacerbated seizures evoked by PTZ, showing that specific efferent projection pathways differentially control different seizure types [248].…”