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Prefrontal Inhibitory Signaling in the Control of Social Behaviors
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Cortical synaptic inhibition is mediated by GABAergic INs, which come with different forms in anatomy, intrinsic membrane properties, synaptic connectivity, and the expression of specific chemical markers (Ascoli et al. 2008; Fishell and Rudy 2011; Rudy et al. 2011; Somogyi and Klausberger 2005). The striking diversity in cellular and synaptic features strongly suggests the existence of functional differentiation among subtypes of cortical INs. However, previous methodological limitations hampered the dissection of functional specialization of subpopulations of GABAergic INs in animal behaviors including social interaction. With the advent of transgenetic mice with subtypes of INs labeled and the development of multiple experimental techniques such as optogenetics, pharmacogenetics, and electrophysiological recordings, neuroscientists are now able to parse out the contribution of specific IN subtypes in cortical computations.
The anterior thalamus and the pentylenetetrazol (PTZ) model
Published in Hans O Lüders, Deep Brain Stimulation and Epilepsy, 2020
Marek A Mirski, David L Sherman, Wendy C Ziai
The synaptic inhibition hypothesis suggests that DBS primarily activates axon terminals that synapse on neurons in the vicinity of the stimulating electrode and in turn modulate the local neural output. There exist large numbers of GABAergic terminals in the thalamus and basal ganglia, and activation of these axon ter-minals by high frequency stimulus trains may inhibit activity in postsynaptic cells via summation of inhibitory postsynaptic potentials (IPSPs) and decreasing the membrane resistance.63–65 Further support for the hypothesis of synaptic inhibition comes from a temporal analysis of postsynaptic effects and stimulus frequency. At higher frequencies (>80 Hz) tremor is suppressed, with a nadir in the stimulus frequency tuning curve at ~125 Hz.66 The time course of GABAergic IPSPs matches well with optimal summation occurring at stimulus frequencies where DBS is most effective. The hypothesis that DBS causes inhibition by excitation of inhibitory afferents to the target structure requires that presynaptic elements be stimulated preferentially by DBS since the neu-rotransmitter-mediated inhibitory effects could be bypassed by direct excitation of the postsynaptic cell. Recent theoretical investigations have shown that threshold for activation of presynaptic terminals for most electrode positions, is lower than the threshold for direct excitation of local postsynaptic cells or fibers of passage.67
Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials
Published in Expert Opinion on Emerging Drugs, 2022
Amanda W Pong, Jonathan Ross, Ivana Tyrlikova, Alexander J Giermek, Maya P Kohli, Yousef A Khan, Roger D Salgado, Pavel Klein
Status epilepticus (SE) is defined as a seizure with 5 min or more of continuous clinical and/or electrographic seizure activity or recurrent seizure activity without recovery between seizures [80]. Refractory status epilepticus (RSE) is defined as SE that is refractory to benzodiazepines and one anti-epileptic drug, lasting > 1 hour [81]. Under normal conditions, there is recycling of the synaptic GABA-A receptors from the synapse to the cytosol and back. In seizures lasting 30–45 min or longer, the recycling starts to fail. GABA-A receptors are cycled from the synapse to the cytosol, but are not replaced. This results in decreased number of GABA-A receptors at the synapse, with resulting decreased GABA-ergic post-synaptic inhibition and loss of efficacy of GABA-ergic ASMs such as benzodiazepines, the standard treatment of SE [82]. As noted above, ganaxolone activates not only the synaptic but also the parasynaptic GABA-A receptors which are not reduced in RSE. Thus, it may continue to be effective in RSE where benzodiazepines and the GABA-ergic medications lose efficacy [82].
Combination Effects of Forced Mild Exercise and GABAB Receptor Agonist on Spatial Learning, Memory, and Motor Activity in Striatum Lesion Rats
Published in Journal of Motor Behavior, 2019
Shaghayegh Modaberi, Soomaayeh Heysieattalab, Mehdi Shahbazi, Nasser Naghdi
Our experiment concluded that interaction treatment of drug and exercise could improve spatial learning and memory by IA-induced striatum lesion in an animal model. Previous studies showed that physical exercise causes neurogenesis, cell proliferation, and dendritic branching (Berchtold, Castello, & Cotman, 2010; Cassilhas et al., 2016; Petzinger et al., 2013; Petzinger et al., 2010). It is also interesting to note that such benefits of exercise might be the result of increased endogenous neurotrophic factors (Wu et al., 2011). It has previously been reported that hippocampal BDNF and NGF protein levels are below control levels 6 weeks after exercise (8 weeks swimming, 5×/week) (Radak et al., 2006). Exercise-induced changes in the AMPA-R, as it is responsible for the majority of fast excitatory neurotransmission in the CNS and mediates activity-dependent processes that alter synaptic strength (Isaac, Ashby, & McBain, 2007). Slow synaptic inhibition is mediated by metabotropic GABAB receptors and it can be activated directly by GABA binding, and facilitate postsynaptic action potential. Baclofen produces slow presynaptic inhibition by inhibiting Ca2+ channels, while postsynaptic GABAB receptors induce a slow inhibitory postsynaptic current, activating G protein-coupled inwardly rectifying K+ (GIRK) channels (Kim & Seo, 2014; Ladera et al., 2008). So, Baclofen microinjection in the GPi through modulating direct pathway and following final output of BG had a subsidiary role in our experiment for helping exercise program and improving spatial learning and motor activity (Kim & Seo, 2014; Nourjah et al., 2006).
Aberrant plasticity in the hippocampus after neonatal seizures
Published in International Journal of Neuroscience, 2018
Xiaoqian Zhang, Huiling Qu, Ying Wang, Shanshan Zhao, Ting Xiao, Chuansheng Zhao, Weiyu Teng
GABA is one of the major inhibitory neurotransmitters in the mature brain. GABA sensitizes chloride channels and thus causes membrane hyperpolarization leading to synaptic inhibition. However, GABA receptors have different functions in mature or immature neurons according to the gradient of intracellular and extracellular chloride ions, which is maintained by chloride transporters such as the Na+-K+−2Cl− cotransporter 1 (NKCC1) and K+-Cl− cotransporter 2 (KCC2) [69,70]. The function of GABA in the immature brain is excitatory and depolarizing [70,71].