Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a... more Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a seizure and allow its evolution remain underexplored. To dissect out phases implicated in the development of a seizure, we evoked hypersynchronous activity with optogenetic stimulation. Focal optogenetic activation of putative excitatory neurons in the mouse hippocampal CA1 reliably evoked convulsive seizures in awake mice. A novel time-vs-time “pulsogram” plot characterized the evolution of the EEG pulse response from a light evoked response to induced seizure activity. Our results depict ictogenesis as a stepwiseprocess comprised of three distinctive phases demarcated by two transition points. The induction phase undergoes the first transition to reverberant phase activity, followed by the second transition into the paroxysmal phase or a seizure. Non-seizure responses are confined to either induction or reverberant phases, suggesting ictogenesis can be stopped at these stages, thus of...
Epilepsy can be interpreted as altered brain rhythms from overexcitation or insufficient inhibiti... more Epilepsy can be interpreted as altered brain rhythms from overexcitation or insufficient inhibition. Chemogenetic tools have revolutionized neuroscience research because they allow “on demand” excitation or inhibition of neurons with high cellular specificity. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are the most frequently used chemogenetic techniques in epilepsy research. These engineered muscarinic receptors allow researchers to excite or inhibit targeted neurons with exogenous ligands. As a result, DREADDs have been applied to investigate the underlying cellular and network mechanisms of epilepsy. Here, we review the existing literature that has applied DREADDs to understand the pathophysiology of epilepsy. The aim of this review is to provide a general introduction to DREADDs with a focus on summarizing the current main findings in experimental epilepsy research using these techniques. Furthermore, we explore how DREADDs may be applied therapeuticall...
doi: 10.3389/fnins.2014.00246 Glutamate reduces glucose utilization while concomitantly enhancing... more doi: 10.3389/fnins.2014.00246 Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons
Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR... more Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.
Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, suc... more Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, such as traumatic brain injury, cerebrovascular insult, or infections. After an insult, the brain enters a period during which progressive neurobiologic alterations convert a non-epileptic brain into a brain capable of generating spontaneous and recurrent seizures, which are defined as epilepsy. The series of events is known as epileptogenesis. Epigenetic (DNA methylation) changes may affect several genes thought to represent risk factors for epilepsy; epigenetic changes are potentially reversible and may constitute a novel target for therapeutic intervention. DNA hypermethylation related to adenosine deficiency results in a vicious cycle associated with the onset of epileptogenesis and leading to chronic pharmacoresistant epilepsy. DNA hypermethylation is restored by the ketogenic diet (KD) via adenosine augmentation, a shift in the S-adenosylhomocysteine and S-adenosylmethionine homeostas...
Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a... more Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a seizure and allow its evolution remain underexplored. To dissect out phases implicated in the development of a seizure, we evoked hypersynchronous activity with optogenetic stimulation. Focal optogenetic activation of putative excitatory neurons in the mouse hippocampal CA1 reliably evoked convulsive seizures in awake mice. A novel time-vs-time “pulsogram” plot characterized the evolution of the EEG pulse response from a light evoked response to induced seizure activity. Our results depict ictogenesis as a stepwiseprocess comprised of three distinctive phases demarcated by two transition points. The induction phase undergoes the first transition to reverberant phase activity, followed by the second transition into the paroxysmal phase or a seizure. Non-seizure responses are confined to either induction or reverberant phases, suggesting ictogenesis can be stopped at these stages, thus of...
Epilepsy can be interpreted as altered brain rhythms from overexcitation or insufficient inhibiti... more Epilepsy can be interpreted as altered brain rhythms from overexcitation or insufficient inhibition. Chemogenetic tools have revolutionized neuroscience research because they allow “on demand” excitation or inhibition of neurons with high cellular specificity. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are the most frequently used chemogenetic techniques in epilepsy research. These engineered muscarinic receptors allow researchers to excite or inhibit targeted neurons with exogenous ligands. As a result, DREADDs have been applied to investigate the underlying cellular and network mechanisms of epilepsy. Here, we review the existing literature that has applied DREADDs to understand the pathophysiology of epilepsy. The aim of this review is to provide a general introduction to DREADDs with a focus on summarizing the current main findings in experimental epilepsy research using these techniques. Furthermore, we explore how DREADDs may be applied therapeuticall...
doi: 10.3389/fnins.2014.00246 Glutamate reduces glucose utilization while concomitantly enhancing... more doi: 10.3389/fnins.2014.00246 Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons
Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR... more Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.
Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, suc... more Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, such as traumatic brain injury, cerebrovascular insult, or infections. After an insult, the brain enters a period during which progressive neurobiologic alterations convert a non-epileptic brain into a brain capable of generating spontaneous and recurrent seizures, which are defined as epilepsy. The series of events is known as epileptogenesis. Epigenetic (DNA methylation) changes may affect several genes thought to represent risk factors for epilepsy; epigenetic changes are potentially reversible and may constitute a novel target for therapeutic intervention. DNA hypermethylation related to adenosine deficiency results in a vicious cycle associated with the onset of epileptogenesis and leading to chronic pharmacoresistant epilepsy. DNA hypermethylation is restored by the ketogenic diet (KD) via adenosine augmentation, a shift in the S-adenosylhomocysteine and S-adenosylmethionine homeostas...
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