Localization of chloride co-transporters in striatal neurons

Tapia, Dagoberto; Suárez, Paola; Arias-García, Mario A.; García-Vilchis, Brisa; Serrano-Reyes, Miguel; Bargas, José; Galarraga, Elvira

doi:10.1097/wnr.0000000000001234

Cited by 5 publications

(4 citation statements)

References 20 publications

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“…Our findings at both single neuron and population levels can explain apparently paradoxical effects reported in the experimental literature. In the adult striatum, GABA reversal potentials are believed to be relatively high in spiny projection neurons (SPNs) [ 29 , 39 , 40 ], which could be due to low levels of the KCC2 co-transporter expression in this cell type [ 42 ]. This high GABA reversal potential can explain several results in in vitro preparations: In particular, why GABA synaptic inputs can sometimes potentiate the response of SPNs to glutamatergic inputs, depending on the relative timing between the two current types [ 40 ], and also why pharmacological inhibition of FSIs can reduce such responses [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

et al. 2022

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GABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that GABAergic synaptic conductance and output firing rate exhibit three qualitatively different regimes as a function of GABA reversal potential, EGABA: monotonically decreasing for sufficiently low EGABA (inhibitory), monotonically increasing for EGABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of EGABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of EGABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.

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Section: Discussionmentioning

confidence: 99%

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

et al. 2022

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“…Our findings at both single neuron and population levels can explain apparently paradoxical effects reported in the experimental literature. In the adult striatum, GABA reversal potentials are believed to be relatively high in spiny projection neurons (SPNs) [30, 40, 41], which could be due to low levels of the KCC2 co-transporter expression in this cell type [43]. This high GABA reversal potential can explain several results in in vitro preparations: In particular, why GABA synaptic inputs can sometimes potentiate the response of SPNs to glutamatergic inputs, depending on the relative timing between the two current types [41], and also why pharmacological inhibition of FSIs can reduce such responses [14].…”

Section: Discussionmentioning

confidence: 99%

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

Zadeh

Turner

Calakos

et al. 2021

Preprint

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GABA is canonically known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyper-polarizing membrane potential. However, GABAergic currents can also exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that the relationship between GABAergic synaptic conductance and output firing rate exhibits three qualitatively different regimes as a function of GABA reversal potential, νGABA: monotonically decreasing for sufficiently low νGABA (inhibitory), monotonically increasing for νGABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of νGABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of νGABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.

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“…Overall, a combination of NKCC1 and KCC2 is expressed in VIP-expressing neurons of the core region in the SCN while NKCC1 and KCC3/4 is found in the AVP-expressing neurons of the shell region. Interestingly, reports that putatively restrict KCC2 to neuronal tissue [33 , 35 , 36] , and confirm NKCC1 to be ubiquitous [37] , [38] , [39] both exist. Taken together, these investigations highlight the importance of NKCC1 and KCC2 in the SCN and suggests a role for them in the circadian system.…”

Section: Expression Of Nkcc1 and Kcc2 In The Scnmentioning

confidence: 99%

Role of the cation-chloride-cotransporters in the circadian system

Salihu

Azlan

Josiah

et al. 2021

Asian Journal of Pharmaceutical Sciences

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Highlights The chloride (Cl-) levels in GABAergic neurons are controlled by two SLC12 cation-chloride-cotransporters (CCCs): Na + /K + /Cl − co-transporter NKCC1 and K + /Cl − co-transporter KCC2, that respectively cause an influx and efflux of Cl-., and thereby controls GABA signalling in the brain. Altered expression and/or activity of either NKCC1 or KCC2 co-transporters in suprachiasmatic nucleus (SCN) have been associated with circadian rhythms. CCCs and their upstream regulators present many promising points of interventions for circadian disruption. 4. A novel strategy has been proposed to facilitate neuronal Cl- extrusion by coincident NKCC1 inhibition and KCC2 activation by inhibiting the WNK3-SPAK/OSR1 signaling pathway with the newly developed SPAK inhibitor, ZT-1a.

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Localization of chloride co-transporters in striatal neurons

Cited by 5 publications

References 20 publications

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

Role of the cation-chloride-cotransporters in the circadian system

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