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

Naomi Lewin, Emre Aksay, Colleen E Clancy

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABAA-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABAA receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABAA-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABAA-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABAA reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K+ transients can augment GABAA-mediated excitation, but not cause it. Our model also suggests the potential for GABAA-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition.

Original languageEnglish (US)
Article numbere47250
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 12 2012

Fingerprint

Pyramidal Cells
interneurons
Interneurons
Neurons
neurons
gamma-aminobutyric acid
Depolarization
synapse
Synapses
gamma-Aminobutyric Acid
Chlorides
Potassium
chlorides
potassium
symporters
Symporters
Temporal Lobe Epilepsy
epilepsy
Neurology
Neuralgia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Computational Modeling Reveals Dendritic Origins of GABAA-Mediated Excitation in CA1 Pyramidal Neurons. / Lewin, Naomi; Aksay, Emre; Clancy, Colleen E.

In: PLoS One, Vol. 7, No. 10, e47250, 12.10.2012.

Research output: Contribution to journalArticle

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