Senescent cell clearance ameliorates temporal lobe epilepsy and associated spatial memory deficits in mice.

Current therapies for the epilepsies only treat the symptoms, but do not prevent epileptogenesis (the process in which epilepsy develops). Many cellular responses during epileptogenesis are also common hallmarks of cellular senescence , which halts proliferation of damaged cells. Clearing senescent cells (SCs) restores function in several age-associated and neurodegenerative disease models. It is unknown whether SC accumulation contributes to epileptogenesis and associated cognitive impairments. To address this question, we used a mouse model of temporal lobe epilepsy (TLE) and characterized the senescence phenotype throughout epileptogenesis. SCs accumulated 2 weeks after SE and were predominantly microglia. We ablated SCs and reduced (and in some cases prevented) the emergence of spontaneous seizures and normalized cognitive function in mice. Suggesting that this is a translationally-relevant target we also found SC accumulation in resected hippocampi from patients with TLE. These findings indicate that SC ablation after an epileptogenic insult is a potential anti-epileptogenic therapy.

Padsevonil suppresses seizures without inducing cell death in neonatal rats.

BACKGROUND: Padsevonil (PSL) is a rationally designed anti-seizure medication (ASM) which has overlapping mechanisms of action with the two most common ASMs used for neonatal seizures, phenobarbital (PB) and levetiracetam (LEV). Here we evaluated the anti-seizure properties of PSL across the neonatal and adolescent period in rats in the pentlyenetetrazole (PTZ) induced seizures model. METHODS: Postnatal day (P)7, P14 and P21 Sprague-Dawley rat pups were pre-treated with PSL (1-30 mg/kg), and assessed for seizure latency and severity 30 min later following injection of PTZ. A separate cohort of P7 pups were treated with neonatal ASMs and euthanized 24 h later (on P8) to assess induction of cell death, a feature common to many ASMs when given to P7 rodents. This effect has been extensively reported with PB, but not with LEV. Cell death was assessed by PathoGreen staining. RESULTS: PSL suppressed PTZ-evoked seizures across multiple age groups, particularly at higher doses, without producing increased cell death compared to vehicle. The effects of PSL were particularly notable at suppressing tonic-clonic seizure manifestations (82% of P7 and 100% of P14 and P21 animals were protected from tonic-clonic seizures with the 30 mg/kg dose). CONCLUSIONS: PSL displayed dose-dependent anti-seizure effects in immature rodents in the PTZ model of seizures in immature rats. While many ASMs, including PB, induce cell death in neonatal rats, PSL does not. This suggests that PSL may offer therapeutic benefit and a favorable safety profile for the treatment of neonatal seizures.

Cenobamate suppresses seizures without inducing cell death in neonatal rats.

GABA modulators such as phenobarbital (PB) and sodium channel blockers such as phenytoin (PHT) have long been the mainstay of pharmacotherapy for the epilepsies. In the context of neonatal seizures, both PB and PHT display incomplete clinical efficacy. Moreover, in animal models, neonatal exposure to these medications result in neurodegeneration raising concerns about safety. Cenobamate, a more recently approved medication, displays unique pharmacology as it is both a positive allosteric modulator of GABA-A receptors, and a voltage-gated sodium channel blocker. While cenobamate is approved for adult use, its efficacy and safety profile against neonatal seizures is poorly understood. To address this gap, we assessed the efficacy and safety of cenobamate in immature rodents. Postnatal day (P)7 rat pups were pretreated with cenobamate and challenged with the chemoconvulsant pentylenetetrazole (PTZ) to screen for anti-seizure effects. In a separate experiment, P7 rats were treated with cenobamate, and brains were processed to assess induction of cell death. Cenobamate displays dose-dependent anti-seizure efficacy in neonatal rats. Unlike PHB and PHT, it does not induce neurotoxicity in P7 rats. Thus, cenobamate may be effective at treating neonatal seizures while avoiding unwanted neurotoxic side effects such as cell death.

Focal pharmacological manipulation of serotonin signaling in the amygdala does not alter social behavior.

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of drugs that increase serotonin signaling is associated with decreased social interactions. However, in primates, the direct involvement of serotonin signaling in the amygdala, particularly in affiliative social interaction, remains unexplored. Here, we examined the effects of serotonin manipulations within the amygdala on social behavior in eight pairs of familiar male macaques. We microinfused drugs targeting the serotonin system into either the basolateral (BLA) or central (CeA) amygdala and measured changes in social behavior. Surprisingly, the results demonstrated no significant differences in social behavior following the infusion of a selective serotonin reuptake inhibitor, 5-HT1A agonist or antagonist, 5-HT2A agonist or antagonist, or 5-HT3 agonist or antagonist into either the BLA or CeA. These findings suggest that serotonin signaling in the amygdala does not directly contribute to the regulation of social behavior between familiar conspecifics. Future research should explore alternative mechanisms and potential interactions with other brain regions to gain a comprehensive understanding of the complex neural circuitry governing social behavior.

Prophylactic senolytic treatment in aged mice reduces seizure severity and improves survival from Status Epilepticus.

Increased vulnerability to seizures in aging has been well documented both clinically and in various models of aging in epilepsy. Seizures can exacerbate cognitive decline that is already prominent in aging. Senescent cells are thought to contribute to cognitive impairment in aging and clearing senescent cells with senolytic drugs improves cognitive function in animal models. It remains unclear whether senescent cells render the aged brain vulnerable to seizures. Here, we demonstrate that prophylactic senolytic treatment with Dasatinib and Quercetin (D&Q) reduced both seizure severity and mortality in aged C57BL/6J mice. We subjected the D&Q and VEH-treated aged mice to spatial memory testing before and after an acute seizure insult, Status Epilepticus [SE], which leads to epilepsy development. We found that senolytic therapy improved spatial memory before injury, however, spatial memory was not rescued after SE. Senescence-related proteins p16 and senescence-associated ß-galactosidase were reduced in D&Q-treated aged mice. Our findings indicate that senescent cells increase seizure susceptibility in aging. Thus, prophylactically targeting senescent cells may prevent age-related seizure vulnerability.

Early life phenobarbital exposure dysregulates the hippocampal transcriptome.

Introduction: Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Methods: Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72 h later-at time at which drug is expected to be cleared. Results: We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers pvalb and opalin, and increased the marker of activated microglia, cd68 and the astrocyte- associated gene vegfa. These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. Discussion: The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity.

Pharmacological Inhibition of the Nucleus Accumbens Increases Dyadic Social Interaction in Macaques.

The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties of social stimuli have a vital role in guiding behavior (both in humans and nonhuman animals), the NAc is likely to contribute to the brain circuitry controlling social behavior. In rodents, prior studies have found that focal pharmacological inhibition of NAc and/or elevation of dopamine in NAc increases social interactions. However, the role of the NAc in social behavior in nonhuman primates remains unknown. We measured the social behavior of eight dyads of male macaques following (1) pharmacological inhibition of the NAc using the GABAA agonist muscimol and (2) focal application of quinpirole, an agonist at the D2 family of dopamine receptors. Transient inhibition of the NAc with muscimol increased social behavior when drug was infused in submissive, but not dominant partners of the dyad. Focal application of quinpirole was without effect on social behavior when infused into the NAc of either dominant or submissive subjects. Our data demonstrate that the NAc contributes to social interactions in nonhuman primates.

Hippocampal lesions impair non-navigational spatial memory in macaques.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks-which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.

Anti-seizure medication-induced developmental cell death in neonatal rats is unaltered by history of hypoxia.

BACKGROUND: Many anti-seizure medications (ASMs) trigger neuronal cell death when administered during a confined period of early life in rodents. Prototypical ASMs used to treat early-life seizures such as phenobarbital induce this effect, whereas levetiracetam does not. However, most prior studies have examined the effect of ASMs in naïve animals, and the degree to which underlying brain injury interacts with these drugs to modify cell death is poorly studied. Moreover, the degree to which drug-induced neuronal cell death differs as a function of sex is unknown. METHODS: We treated postnatal day 7 Sprague Dawley rat pups with vehicle, phenobarbital (75 mg/kg) or levetiracetam (200 mg/kg). Separate groups of pups were pre-exposed to either normoxia or graded global hypoxia. Separate groups of males and females were used. Twenty-four hours after drug treatment, brains were collected and processed for markers of cell death. RESULTS: Consistent with prior studies, phenobarbital, but not levetiracetam, increased cell death in cortical regions, basal ganglia, hippocampus, septum, and lateral thalamus. Hypoxia did not modify basal levels of cell death. Females - collapsed across treatment and hypoxia status, displayed a small but significant increase in cell death as compared to males in the cingulate cortex, somatosensory cortex, and the CA1 and CA3 hippocampus; these effects were not modulated by hypoxia or drug treatment. CONCLUSION: We found that a history of graded global hypoxia does not alter the neurotoxic profile of phenobarbital. Levetiracetam, which does not induce cell death in normal developing animals, maintained a benign profile on the background of neonatal hypoxia. We found a sex-based difference, as female animals showed elevated levels of cell death across all treatment conditions. Together, these data address several long-standing gaps in our understanding of the neurotoxic profile of antiseizure medications during early postnatal development.

Restoration of norepinephrine release, cognitive performance, and dendritic spines by amphetamine in aged rat brain.

Age-related dysfunctions in specific neurotransmitter systems likely play an important role in cognitive decline even in its most subtle forms. Therefore, preservation or improvement of cognition via augmentation of neurotransmission is a potential therapeutic strategy to prevent further cognitive deficits. Here we identified a particular neuronal vulnerability in the aged Fischer 344 rat brain, an animal model of neurocognitive aging. Specifically, we demonstrated a marked impairment in glutamate-stimulated release of norepinephrine (NE) in the hippocampus and cerebral cortex of aged rats, and established that this release was mediated by N-methyl-D-aspartate (NMDA) receptors. Further, we also demonstrated that this decrease in NE release is fully rescued by the psychostimulant drug amphetamine (AMPH). Moreover, we showed that AMPH increases dendritic spine maturation, and importantly shows preclinical efficacy in restoring memory deficits in the aged rat through its actions to potentiate NE neurotransmission at ß-adrenergic receptors. Taken together, our results suggest that deficits in glutamate-stimulated release of NE may contribute to and possibly be a determinant of neuronal vulnerability underlying cognitive decline during aging, and that these deficits can be corrected with currently available drugs. Overall these studies suggest that repurposing of psychostimulants for age-associated cognitive deficits is a potential avenue to delay or prevent cognitive decline and/or frank dementia later in life.

The effects of a dual orexin receptor antagonist on fear extinction memory and sleep in mice: Implications for exposure therapy.

Extinction of conditioned fear is considered a fundamental process in the recovery from posttraumatic stress disorder and anxiety disorders. Sleep, especially rapid-eye-movement (REM) sleep, has been implicated in promoting extinction memory. The orexin system contributes to the regulation of sleep and wakefulness and emotional behaviors. In rodents, administrations of an orexin receptor antagonist following fear extinction training enhanced consolidation of extinction memory. Although orexin antagonists increase sleep, including REM sleep, the possible contribution of sleep to the effects of orexin antagonists on extinction memory has not been examined. Therefore, this study examined the effects of suvorexant, a dual orexin receptor antagonist, on extinction memory and sleep and their associations in mice. C57BL/6 mice underwent sleep recording for 24 h before and after contextual fear conditioning with footshocks and extinction learning during the early light phase or early dark phase. Mice were systemically injected with either 25 mg/kg of suvorexant or vehicle immediately after the extinction session. We found that suvorexant neither altered sleep nor improved extinction memory recall compared with vehicle. The higher percentages of REM sleep during the post-extinction dark phase were associated with lower extinction memory recall and greater freezing responses to the fear context. Results also indicate that animals did not reach complete extinction of fear with the fear extinction training protocol used in this study. These findings suggest that promoting REM sleep may not enhance fear extinction memory when extinction of fear is incomplete.

Phenobarbital does not worsen outcomes of neonatal hypoxia on hippocampal LTP on rats.

Introduction: Neonatal hypoxia is a common cause of early-life seizures. Both hypoxia-induced seizures (HS), and the drugs used to treat them (e.g., phenobarbital, PB), have been reported to have long-lasting impacts on brain development. For example, in neonatal rodents, HS reduces hippocampal long-term potentiation (LTP), while PB exposure disrupts GABAergic synaptic maturation in the hippocampus. Prior studies have examined the impact of HS and drug treatment separately, but in the clinic, PB is unlikely to be given to neonates without seizures, and neonates with seizures are very likely to receive PB. To address this gap, we assessed the combined and separate impacts of neonatal HS and PB treatment on the development of hippocampal LTP. Methods: Male and female postnatal day (P)7 rat pups were subjected to graded global hypoxia (or normoxia as a control) and treated with either PB (or vehicle as a control). On P13-14 (P13+) or P29-37 (P29+), we recorded LTP of the Schaffer collaterals into CA1 pyramidal layer in acute hippocampal slices. We compared responses to theta burst stimulation (TBS) and tetanization induction protocols. Results: Under the TBS induction protocol, female rats showed an LTP impairment caused by HS, which appeared only at P29+. This impairment was delayed compared to male rats. While LTP in HS males was impaired at P13+, it normalized by P29+. Under the tetanization protocol, hypoxia produced larger LTP in males compared to female rats. PB injection, under TBS, did not exacerbate the effects of hypoxia. However, with the tetanization protocol, PB - on the background of HS - compensated for these effects, returning LTP to control levels. Discussion: These results point to different susceptibility to hypoxia as a function of sex and age, and a non-detrimental effect of PB when administered after hypoxic seizures.

Optogenetic stimulation of the superior colliculus suppresses genetic absence seizures.

While anti-seizure medications are effective for many patients, nearly one-third of individuals have seizures that are refractory to pharmacotherapy. Prior studies using evoked preclinical seizure models have shown that pharmacological activation or excitatory optogenetic stimulation of the deep and intermediate layers of the superior colliculus (DLSC) display multi-potent anti-seizure effects. Here we monitored and modulated DLSC activity to suppress spontaneous seizures in the WAG/Rij genetic model of absence epilepsy. Female and male WAG/Rij adult rats were employed as study subjects. For electrophysiology studies, we recorded single unit activity from microwire arrays placed within the DLSC. For optogenetic experiments, animals were injected with virus coding for channelrhodopsin-2 or a control vector, and we compared the efficacy of continuous neuromodulation to that of closed-loop neuromodulation paradigms. For each, we compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). For closed-loop stimulation, we detected seizures in real time based on the EEG power within the characteristic frequency band of spike-and-wave discharges (SWDs). We quantified the number and duration of each SWD during each 2 h-observation period. Following completion of the experiment, virus expression and fibre-optic placement was confirmed. We found that single-unit activity within the DLSC decreased seconds prior to SWD onset and increased during and after seizures. Nearly 40% of neurons displayed suppression of firing in response to the start of SWDs. Continuous optogenetic stimulation of the DLSC (at each of the three frequencies) resulted in a significant reduction of SWDs in males and was without effect in females. In contrast, closed-loop neuromodulation was effective in both females and males at all three frequencies. These data demonstrate that activity within the DLSC is suppressed prior to SWD onset, increases at SWD onset, and that excitatory optogenetic stimulation of the DLSC exerts anti-seizure effects against absence seizures. The striking difference between open- and closed-loop neuromodulation approaches underscores the importance of the stimulation paradigm in determining therapeutic effects.

Quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition of the acoustic startle in rhesus macaques.

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABAA agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition.

Pharmacological Inactivation of the Bed Nucleus of the Stria Terminalis Increases Affiliative Social Behavior in Rhesus Macaques.

The bed nucleus of the stria terminalis (BNST) has been implicated in a variety of social behaviors, including aggression, maternal care, mating behavior, and social interaction. Limited evidence from rodent studies suggests that activation of the BNST results in a decrease in social interaction between unfamiliar animals. The role of the BNST in social interaction in primates remains wholly unexamined. Nonhuman primates provide a valuable model for studying social behavior because of both their rich social repertoire and neural substrates of behavior with high translational relevance to humans. To test the hypothesis that the primate BNST is a critical modulator of social behavior, we performed intracerebral microinfusions of the GABAA agonist muscimol to transiently inactivate the BNST in male macaque monkeys. We measured changes in social interaction with a familiar same-sex conspecific. Inactivation of the BNST resulted in significant increase in total social contact. This effect was associated with an increase in passive contact and a significant decrease in locomotion. Other nonsocial behaviors (sitting passively alone, self-directed behaviors, and manipulation) were not impacted by BNST inactivation. As part of the "extended amygdala," the BNST is highly interconnected with the basolateral (BLA) and central (CeA) nuclei of the amygdala, both of which also play critical roles in regulating social interaction. The precise pattern of behavioral changes we observed following inactivation of the BNST partially overlaps with our prior reports in the BLA and CeA. Together, these data demonstrate that the BNST is part of a network regulating social behavior in primates.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) has a well-established role in anxiety behaviors, but its role in social behavior is poorly understood. No prior studies have evaluated the impact of BNST manipulations on social behavior in primates. We found that transient pharmacological inactivation of the BNST increased social behavior in pairs of macaque monkeys. These data suggest the BNST contributes to the brain networks regulating sociability.

Preclinical common data elements for general pharmacological studies (pharmacokinetic sample collection, tolerability, and drug administration). A report of the TASK3-WG1A General Pharmacology Working Group of the ILAE/AES Joint Translational Task Force.

Growing concerns over rigor and reproducibility of preclinical studies, including consistency across laboratories and translation to clinical populations, have triggered efforts to harmonize methodologies. This includes the first set of preclinical common data elements (CDEs) for epilepsy research studies, as well as Case Report Forms (CRFs) for widespread use in epilepsy research. The General Pharmacology Working Group of the ILAE/AES Task Force (TASK3-WG1A) has continued in this effort by adapting and refining CDEs/CRFs to address specific study design areas as they relate to preclinical drug screening: general pharmacology, pharmacokinetics (PK) and pharmacodynamics (PD), and tolerability. This work has expanded general pharmacology studies to include dose records, PK/PD, tolerability, and elements of rigor and reproducibility. Tolerability testing CRFs included rotarod and Irwin/Functional Observation Battery (FOB) assays. The material provided in the form of CRFs can be delivered for widespread use within the epilepsy research community.

Cannabidiol attenuates generalized tonic-clonic and suppresses limbic seizures in the genetically epilepsy-prone rats (GEPR-3) strain.

BACKGROUND: Cannabidiol (CBD) has been of rapidly growing interest in the epilepsy research field due to its antiseizure properties in preclinical models and patients with pharmacoresistant epilepsy. However, little is known about CBD effects in genetic models of epilepsies. Here we assessed CBD dose-response effects in the Genetically Epilepsy Prone Rats (GEPR-3) strain, which exhibits two types of epileptic seizures, brainstem-dependent generalized tonic-clonic seizures and limbic seizures. METHODS: GEPR-3 s were submitted to the audiogenic seizure (AGS) protocol. Acute AGS are brainstem-dependent generalized tonic-clonic, while repeated AGS (or audiogenic kindling, AK), an epileptogenic process, leads to increased AGS severity and limbic seizure expression. Therefore, two different dose-response studies were performed, one for generalized tonic-clonic seizures and the other for limbic seizures. CBD time-course effects were assessed 2, 4, and 6 h after drug injection. GEPR-3 s were submitted to within-subject tests, receiving intraperitoneal injections of CBD (1, 10, 50, 100 mg/kg/ml) and vehicle. RESULTS: CBD dose-dependently attenuated generalized tonic-clonic seizures in GEPR-3 s; CBD 50 and 100 mg/kg reduced brainstem-dependent seizure severity and duration. In fully kindled GEPR-3 s, CBD 10 mg/kg reduced limbic seizure severity and suppressed limbic seizure expression in 75% of animals. CONCLUSIONS: CBD was effective against brainstem and limbic seizures in the GEPR-3 s. These results support the use of CBD treatment for epilepsies by adding new information about the pharmacological efficacy of CBD in suppressing inherited seizure susceptibility in the GEPR-3 s.

Optogenetic activation of the superior colliculus attenuates spontaneous seizures in the pilocarpine model of temporal lobe epilepsy.

OBJECTIVE: Decades of studies have indicated that activation of the deep and intermediate layers of the superior colliculus can suppress seizures in a wide range of experimental models of epilepsy. However, prior studies have not examined efficacy against spontaneous limbic seizures. The present study aimed to address this gap through chronic optogenetic activation of the superior colliculus in the pilocarpine model of temporal lobe epilepsy. METHODS: Sprague Dawley rats underwent pilocarpine-induced status epilepticus and were maintained until the onset of spontaneous seizures. Virus coding for channelrhodopsin-2 was injected into the deep and intermediate layers of the superior colliculus, and animals were implanted with head-mounted light-emitting diodes at the same site. Rats were stimulated with either 5- or 100-Hz light delivery. Seizure number, seizure duration, 24-h seizure burden, and behavioral seizure severity were monitored. RESULTS: Both 5- and 100-Hz optogenetic stimulation of the deep and intermediate layers of the superior colliculus reduced daily seizure number and total seizure burden in all animals in the active vector group. Stimulation did not affect either seizure duration or behavioral seizure severity. Stimulation was without effect in opsin-negative control animals. SIGNIFICANCE: Activation of the deep and intermediate layers of the superior colliculus reduces both the number of seizures and total daily seizure burden in the pilocarpine model of temporal lobe epilepsy. These novel data demonstrating an effect against chronic experimental seizures complement a long history of studies documenting the antiseizure efficacy of superior colliculus activation in a range of acute seizure models.

Preclinical efficacy of cannabidiol for the treatment of early-life seizures.

BACKGROUND: The treatment of epilepsy during early life poses unique challenges-first-line therapies leave many individuals with poorly controlled seizures. In response to the pharmaco-resistance of current first-line anti-seizure drugs (ASDs) during early life, new therapies have emerged. One such therapy is cannabidiol (CBD). While well studied in adult models of epilepsy, it is poorly studied in immature animals. Here we assessed the efficacy of CBD in immature rodent models of the epilepsies. METHODS: Pups were pre-treated with CBD (1, 10, 50, 100, 200 mg/kg) and assessed for anticonvulsant efficacy using two well-established anti-seizure screening models: the pentylenetetrazole (PTZ) and maximal electroshock (MES) models. We assessed drug efficacy in postnatal day (P)7 and P21 rats. RESULTS: In the PTZ model, CBD delayed seizure onset in adolescent but not neonatal rats. By contrast, higher doses of CBD reduced seizure duration in both neonatal and adolescent rats in the MES model. The effects of CBD in both models were modest but consistent. CONCLUSION: Efficacy of CBD increased in older as compared to younger animals, producing an age-, model-, and dose-dependent suppression of seizures. These data suggest neonatal seizures (modeled by P7 treatment) may be less responsive to CBD. They also suggest preferential efficacy against tonic seizures as compared to partial motor seizures.

Seizing Control of Neuronal Activity: Chemogenetic Applications in Epilepsy.

The fundamental commonality across pharmacotherapies for the epilepsies is the modulation of neuronal excitability. This poses a clear challenge-patterned neuronal excitation is essential to normal function, thus disrupting this activity leads to side effects. Moreover, the efficacy of current pharmacotherapy remains incomplete despite decades of drug development. Approaches that allow for the selective targeting of critical populations of cells and particular pathways in the brain have the potential to both avoid side effects and improve efficacy. Chemogenetic methods, which combine the selective expression of designer receptors with designer drugs, have rapidly grown in use in the neurosciences, including in epilepsy. This review will briefly highlight the history of chemogenetics, their applications to date in epilepsy, and the potential (and potential hurdles to overcome) for future translation.