Computational Modeling Reveals Dendritic Origins of GABAA-Mediated Excitation in CA1 Pyramidal Neurons

Lewin, Naomi; Aksay, Emre; Clancy, Colleen E.

doi:10.1371/journal.pone.0047250

Cited by 22 publications

(22 citation statements)

References 69 publications

(164 reference statements)

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“…Several investigations have highlighted the anticonvulsant effects of furosemide, but the effects are likely due to inhibition of glial NKCC1 and reductions in glial swelling (Hochman, ), or altered kidney function (Loscher et al ., ). Our investigation supports the inhibitory role of KCC2‐mediated Cl − extrusion in neurons (Jarolimek et al ., ; Lewin et al ., ). Furosemide increased network excitability by abolishing hyperpolarising GABA A signaling and not by inhibiting GABA A receptors.…”

Section: Discussionmentioning

confidence: 97%

Disrupted Cl⁻ homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Deeb

Nakamura

Frost

et al. 2013

Eur J of Neuroscience

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The K+-Cl− cotransporter KCC2 is the major Cl− extrusion mechanism in most adult neurons. This process in turn leads to Cl− influx upon activation of GABAA receptors and the canonical hyperpolarizing inhibitory postsynaptic potential. Several neurological disorders are treated with drugs that target and enhance GABAA receptor signaling, including the commonly used benzodiazepine diazepam and the anesthetic propofol. Some of these disorders are also associated with deficits in GABAA signaling and become less sensitive to therapeutic drugs that target GABAA receptors. To date, it is unknown if alterations in the neuronal Cl− gradient affect the efficacies of diazepam and propofol. We therefore used the in vitro model of glutamate-induced hyperexcitability to test if alterations in the Cl− gradient affect the efficacy of GABAA modulators. We exclusively utilized the gramicidin perforated-patch clamp configuration to preserve the endogenous Cl− gradient. Brief exposure to glutamate reduced the inhibitory efficacy of diazepam within five minutes that was caused by the collapse of the Cl− gradient, and not due to reductions in GABAA receptor number. Unlike diazepam, propofol retained its efficacy by shunting the membrane conductance despite the glutamate-induced appearance of depolarizing GABAA-mediated currents. Similarly, pharmacological inhibition of KCC2 by furosemide disrupted Cl− homeostasis and reduced the efficacy of diazepam but not propofol. Collectively our results suggest pathological hyperexcitable conditions could cause the rapid accumulation of intracellular Cl− and the appearance of depolarizing GABAA-mediated currents that would decrease the efficacy of diazepam.

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Section: Discussionmentioning

confidence: 97%

Disrupted Cl⁻ homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Deeb

Nakamura

Frost

et al. 2013

Eur J of Neuroscience

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“…Therefore, the CCCs are a component of the Gibbs-Donnan system. Their role is to facilitate the movement of Cl − , co-transported cations and water during rapid synaptic activity and therefore, to maintain the equilibrium conditions established by the local immobile anion concentrations [25,48,67,68]. While the [Cl] i set point is determined by the immobile anions on either side of the membrane, the importance of the CCCs in establishing the equilibrium is evidenced by the functional alterations in [Cl − ] i seen in both NKCC1 and KCC2 knockout animals [69–73].…”

Section: Cl−: the Neuronal “Packing Peanut”mentioning

confidence: 99%

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Glykys

Dzhala

Egawa

et al. 2017

Trends in Neurosciences

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Pharmaco-resistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl− concentration ([Cl−]i) regulation impacts both cell volume homeostasis and Cl− permeable GABAA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl−]i –cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl− transporters– could help identify novel anti-convulsive and neuroprotective targets. The cation-Cl− cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. Here, we establish a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl−]i and how these mechanisms impact neuronal volume and excitability. We propose approaches to modulate [Cl−]i that are relevant for two common clinical sequela of brain injury: edema and seizures.

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“…Previous experimental and computational work has demonstrated that for a given Clload via activated synaptic GABAARs, Claccumulation occurs more readily on smaller volume peripheral dendrites than more proximal dendritic and somatic compartments (16,18,19,21). The effect of this on the input-output properties of neurons, however, has not previously been explored.…”

Section: Discussionmentioning

confidence: 99%

“…For example, both experimental and modelling studies have shown how small volume dendritic compartments are particularly prone to ionic plasticity (16,(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

“…Whilst the vast majority of theoretical models of inhibitory signalling and neuronal computation assume static values for EGABA, previous studies have addressed the biophysical underpinnings of Clhomeostasis and ionic plasticity in neurons (20,22), the effects of neuronal morphologies on Claccumulation (19,21,23), and how dynamic Claffects neural coding (24). However, how differences in the spatial targeting of synaptic inhibition interact with ionic plasticity to dynamically modulate the input-output function of neurons is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Chloride dynamics alter the input-output properties of neurons

Currin

Trevelyan

Akerman

et al. 2019

Preprint

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Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal inputoutput function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were entirely mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition. Author SummaryThe fundamental unit of computation in the brain is the neuron, whose output reflects information within the brain. A determining factor in the transfer and processing of information in the brain is the modulation of activity by inhibitory synaptic inputs. Fast synaptic inhibition is mediated by the neurotransmitter GABA binding to GABAA receptors, which are permeable to chloride ions. How changes in chloride ion concentration affect neuronal output is an important consideration for information flow in the brain that is currently not being thoroughly investigated. In this research, we used multi-compartmental models of neurons to link the deleterious effects that accumulation of chloride ions can have on inhibitory signalling with changes in neuronal ouput. Together, our results highlight the importance of accounting for changes in chloride concentration in theoretical and computer-based models that seek to explore the computational properties of inhibition.

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Computational Modeling Reveals Dendritic Origins of GABAA-Mediated Excitation in CA1 Pyramidal Neurons

Cited by 22 publications

References 69 publications

Disrupted Cl⁻ homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Disrupted Cl⁻ homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Chloride dynamics alter the input-output properties of neurons

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Computational Modeling Reveals Dendritic Origins of GABAA-Mediated Excitation in CA1 Pyramidal Neurons

Cited by 22 publications

References 69 publications

Disrupted Cl− homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Disrupted Cl− homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Chloride dynamics alter the input-output properties of neurons

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Product

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Disrupted Cl⁻ homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states

Disrupted Cl⁻ homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states