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The Gap between Intention and Action
Published in Elizabeth B. Torres, Caroline Whyatt, Autism, 2017
Optimal gamma oscillations are produced by delayed feedback and shunting inhibition by fast-spiking, soma-inhibiting, GABAergic basket cells expressing parvalbumin (PV), a robust marker for interneurons, and specialized for GABA-A-mediated conductance (Bartos et al. 2007). Notably, multiple mouse models of autism show a common circuit disruption in PV-positive GABAergic inhibitory interneurons (Gogolla et al. 2009).
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
NKCC1 channels are required for active extrusion and accumulation of Cl-, respectively. Nonetheless, if ClC-2 is transiently transfected into neurons with high intra-cellular Cl-, such as dorsal root ganglion neurons, GABA is no longer depolarizing in these neurons but rather becomes hyperpolarizing due to shunting inhibition and changes in membrane resistance.27 By analogy, ClC-2 expression would be predicted to be low in the early postnatal brain but increase progressively beginning around PN 6 to 10, and this is indeed the case in the neocortex.28 Taken together, these studies demonstrate the critical role played by these three Cl- transporters in determining whether a particular cell’s response to GABA is excitatory or inhibitory.
Comparative Studies of Pyramidal Neurons in Visual Cortex of Monkeys
Published in Jon H. Kaas, Christine E. Collins, The Primate Visual System, 2003
on the other hand, project primarily to the dendrites and somata of the pyramidal cells and are believed to modulate activity within the dendritic arbors via local vetoing, or shunting inhibition.59 Thus, differences in the density and distribution of these different types of interneurons are likely to underlie the regional variation reported in their patterns of connectivity.54,55
Anxiolytics targeting GABAA receptors: Insights on etifoxine
Published in The World Journal of Biological Psychiatry, 2018
Pierrick Poisbeau, Geraldine Gazzo, Laurent Calvel
GABAAR activation is associated with an increase in chloride permeability through the plasma membrane, which is responsible for neuronal inhibition. This inhibition is generally seen as a membrane hyperpolarisation but, alternatively, may also consist of a shunting inhibition due to a local drop in membrane resistance. Both mechanisms reduce the capacity of neurons to produce action potentials or to regenerate these along their progression to synaptic endings. Recent findings have highlighted the importance of chloride gradients and their plasticity in physiological and pathological conditions. Indeed, destruction of these chloride gradients seems to contribute to several hyperexcitable neuropathologies such as epilepsy or neuropathic pain (Coull et al. 2003; Sammler et al. 2015). As illustrated in Figure 1 and Table 1, a large variety of compounds can bind to GABAARs. This includes endogenous modulators (e.g. endozepines and neuroactive steroids such as allopregnanolone) as well as anxiolytics such as benzodiazepines (e.g. diazepam, lorazepam), barbiturates or etifoxine.
Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability
Published in Expert Opinion on Therapeutic Targets, 2020
Phan Q. Duy, Miao He, Zhigang He, Kristopher T. Kahle
In settings of low KCC2 activity, intraneuronal Cl− concentrations are expected to increase due to diminished extrusion capacity, leading to a depolarizing response marked by Cl− efflux following GABAergic input. In other words, these changes can render GABA a paradoxically excitatory rather than an inhibitory neurotransmitter. Although membrane depolarization is usually thought to be excitatory (by bringing membrane potential toward threshold potential), depolarizing GABA can also exert inhibitory actions under specific circumstances due to other mechanisms such as shunting inhibition (see [29,36] for detailed explanation). KCC2 hypofunction has been observed in some physiological settings, such as those during early neural development when KCC2 activity is minimal in young neurons [37,38]. During early postnatal life, KCC2 upregulation in postnatal neurons reduces intracellular chloride concentrations, leading to a reversal of GABAergic responses from depolarization to hyperpolarization [39–41]. Depolarizing GABA in early neural development has been shown to regulate multiple aspects of brain morphogenesis and maturation, including neural stem cell proliferation, migration, and differentiation [42–45]. These functional effects of depolarizing GABA on neural development are thought to be mediated by activation of voltage-gated calcium channels, leading to recruitment of calcium-dependent second-messenger pathways [46,47]. Consequently, by influencing GABA polarity and the attendant signaling cascades, the spatiotemporal dynamics of KCC2 activity constitutes a mechanism that allows developing neuronal cells to execute the appropriate cellular program at the right time in response to developmental cues. The transition from low to high KCC2 activity across neuronal development is regulated at the posttranslational level by reciprocal phosphorylation and dephosphorylation events at critical amino acid residues [48,49] (Figure 2).