Abstract:Epilepsy is often associated with emotional disturbances and the endocannabinoid (eCB) system tunes synaptic transmission in brain regions regulating emotional behavior. Thus, persistent alteration of eCB signaling after repeated seizures may contribute to the development of epilepsy-related emotional disorders. Here we report that repeatedly eliciting seizures (kindling) in the amygdala caused a long-term increase in anxiety and impaired fear memory retention, which was paralleled by an imbalance in GABA/glut… Show more
“…Thus, loss of K v 1.1 subunits does not appear to modify the intrinsic excitability of BLA pyramidal neurons. These data are consistent with previous results showing that kindling or repeated seizures in the amygdala do not alter membrane properties and intrinsic excitability of BLA pyramidal neurons 45 , 46 . Figure 1 Lack of effect of K v 1.1 deletion on the intrinsic excitability of BLA pyramidal neurons.…”
Section: Resultssupporting
confidence: 93%
“…2 d). These data suggest that the increase in sEPSCs frequency observed in Kcna1 −/− BLA neurons is likely a result of an increased glutamate release probability at nerve terminals, consistent with previous reports of synaptic activity of BLA neurons from kindled rats 46 . We next recorded sIPSCs (Fig.…”
Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking Kv1.1 subunits (Kcna1−/−) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in Kcna1−/− mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. Yet, the functional alterations leading to amygdala hyperexcitability have not been identified. In this study, we used Kcna1−/− mice to examine the contributions of Kv1.1 subunits to excitability in neuronal subtypes from basolateral (BLA) and central lateral (CeL) amygdala known to exhibit distinct firing patterns. We also analyzed synaptic transmission properties in an amygdala local circuit predicted to be involved in epilepsy-related comorbidities. Our data implicate Kv1.1 subunits in controlling spontaneous excitatory synaptic activity in BLA pyramidal neurons. In the CeL, Kv1.1 loss enhances intrinsic excitability and impairs inhibitory synaptic transmission, notably resulting in dysfunction of feed-forward inhibition, a critical mechanism for controlling spike timing. Overall, we find inhibitory control of CeL interneurons is reduced in Kcna1−/− mice suggesting that basal inhibitory network functioning is less able to prevent recurrent hyperexcitation related to seizures.
“…Thus, loss of K v 1.1 subunits does not appear to modify the intrinsic excitability of BLA pyramidal neurons. These data are consistent with previous results showing that kindling or repeated seizures in the amygdala do not alter membrane properties and intrinsic excitability of BLA pyramidal neurons 45 , 46 . Figure 1 Lack of effect of K v 1.1 deletion on the intrinsic excitability of BLA pyramidal neurons.…”
Section: Resultssupporting
confidence: 93%
“…2 d). These data suggest that the increase in sEPSCs frequency observed in Kcna1 −/− BLA neurons is likely a result of an increased glutamate release probability at nerve terminals, consistent with previous reports of synaptic activity of BLA neurons from kindled rats 46 . We next recorded sIPSCs (Fig.…”
Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking Kv1.1 subunits (Kcna1−/−) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in Kcna1−/− mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. Yet, the functional alterations leading to amygdala hyperexcitability have not been identified. In this study, we used Kcna1−/− mice to examine the contributions of Kv1.1 subunits to excitability in neuronal subtypes from basolateral (BLA) and central lateral (CeL) amygdala known to exhibit distinct firing patterns. We also analyzed synaptic transmission properties in an amygdala local circuit predicted to be involved in epilepsy-related comorbidities. Our data implicate Kv1.1 subunits in controlling spontaneous excitatory synaptic activity in BLA pyramidal neurons. In the CeL, Kv1.1 loss enhances intrinsic excitability and impairs inhibitory synaptic transmission, notably resulting in dysfunction of feed-forward inhibition, a critical mechanism for controlling spike timing. Overall, we find inhibitory control of CeL interneurons is reduced in Kcna1−/− mice suggesting that basal inhibitory network functioning is less able to prevent recurrent hyperexcitation related to seizures.
“…The endocannabinoid system has been consistently reported to modulate fear memory extinction and stress/fear coping strategies, in male rodents (Colangeli, Morena, Pittman, Hill, & Teskey, 2020; Gunduz‐Cinar et al, 2013; Heinz, Genewsky, & Wotjak, 2017; Llorente‐Berzal et al, 2015; Marsicano et al, 2002; Metna‐Laurent et al, 2012; Morena et al, 2016, 2019, 2018). Increased AEA has been shown to promote fear extinction by reducing expression of freezing (Bitencourt, Pamplona, & Takahashi, 2008; Chhatwal, Davis, Maguschak, & Ressler, 2005; Gunduz‐Cinar et al, 2013; Marsicano et al, 2002; Pamplona, Bitencourt, & Takahashi, 2008) via activation of CB 1 receptors on forebrain glutamatergic neurons (Llorente‐Berzal et al, 2015).…”
Section: Discussionmentioning
confidence: 99%
“…The endocannabinoid system has been consistently reported to modulate fear memory extinction and stress/fear coping strategies, in male rodents (Colangeli, Morena, Pittman, Hill, & Teskey, 2020;Gunduz-Cinar et al, 2013;Heinz, Genewsky, & Wotjak, 2017;Llorente-Berzal et al, 2015;Marsicano et al, 2002;Metna-Laurent et al, 2012;Morena et al, , 2019.…”
Background and Purpose: Women are twice as likely as men to develop posttraumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. Experimental Approach: To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. Key Results: Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid 1 (CB 1) receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex-and brain region-specific changes. Conclusion and Implications: We provide the first evidence that AEA and 2-AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex-specific therapeutics to treat trauma-related disorders.
“… 136 , 137 The presence of these compounds in the neuronal environment and at the site of synaptic communication can cause modulatory effects on these cells’ properties and performance. 138 , 139 Most anandamides are produced by N-acyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD) enzymes inside the cell and then transported to the extracellular space. The fatty-acid amide hydrolase (FAAH) enzyme is responsible for metabolizing and removing accumulated anandamides.…”
Section: The Effect Of Endo-cannabinoids Inhibitorsmentioning
Epilepsies are among the most common neurological problems. The disease burden in patients with epilepsy is significantly high, and epilepsy has a huge negative impact on patients’ quality of life with epilepsy and their families. Anti-seizure medications are the mainstay treatment in patients with epilepsy, and around 70% of patients will ultimately control with a combination of at least two appropriately selected anti-seizure medications. However, in one-third of patients, seizures are resistant to drugs, and other measures will be needed. The primary goal in using experimental therapeutic medication strategies in patients with epilepsy is to prevent recurrent seizures and reduce the rate of traumatic events that may occur during seizures. So far, various treatments using medications have been offered for patients with epilepsies, which have been classified according to the type of epilepsy, the effectiveness of the medications, and the adverse effects. Medications such as Levetiracetam, valproic acid, and lamotrigine are at the forefront of these patients’ treatment. Epilepsy surgery, neuro-stimulation, and the ketogenic diet are the main measures in patients with medication-resistant epilepsies. In this paper, we will review the therapeutic approach using anti-seizure medications in patients with epilepsy. However, it should be noted that some of these patients still do not respond to existing treatments; therefore, the limited ability of current therapies has fueled research efforts for the development of novel treatment strategies. Thus, it seems that in addition to surgical measures, we should look for more specific agents that have less adverse events and have a greater effect in stopping seizures.
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