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

Clancy CE (2012) Computational Modeling Reveals Dendritic Origins of GABAA-Mediated Excitation in CA1 Pyramidal Neurons. PLoS ONE 7(10): e47250. doi:10.1371/journal.pone.0047250 Computational Modeling Reveals Dendritic Origins of GABAA-Mediated Excitation in CA1 Pyramidal Neurons Naomi Lewin 0 Emre Aksay 0 Colleen E. Clancy 0 Maxim Bazhenov, University of California Riverside, United States of America 0 1 Department of Physiology and Biophysics, Weill Medical College of Cornell University , New York , New York, United States of America, 2 Tri-Institutional MD-PhD Program, Physiology, Biophysics and Systems Biology Graduate Program, Department of Pharmacology, University of California Davis , Davis, California , United States of America 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 cotransporter 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. - Funding: Supported by the American Heart Association (AHA) (GIA, Western States Affiliate), the Alfred P. Sloan Foundation and the National Institutes of Health (NIH) NHLBI RO1-HL-085592-05 and NHLBI RO1-HL-085592-S2 (to CEC, MSTP grant: 5 T 32 GM 07739 (NL), The Searle Scholars Program, Burroughs Wellcome Fund and NIH NEI 1R01EY021581-01 (to EA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Despite widespread acceptance of GABA as the transmitter of inhibition in the central nervous system, there is plentiful evidence that GABA can also cause pathological excitation in the cortex. GABAA-mediated excitation has been suggested as a potential mechanism in diseases of neuronal hyperexcitability, such as epilepsy and neuropathic pain, and in neuroendocrine responses to stress [13]. Determining the mechanisms of GABAA-mediated excitation and its role in triggering pathological excitation may allow identification of new therapeutic targets to treat diseases of excitability. In experimental slice preparations with glutamatergic blockade, synaptic activation of GABAA receptors at frequencies that mimic rapid physiological firing leads to a reproducible cellular level phenomenon in isolated post-synaptic CA1 pyramidal neurons - paradoxical excitatory depolarization following the expected hyperpolarization [45]. This paradoxical depolarization is the apparent trigger that precedes neuronal firing and network synchrony in slices with intact glutamatergic transmission [6]. Although numerous experimental studies have attempted to reveal the underlying ionic mechanisms of GABAA-mediated excitation in CA1 pyramidal neurons, the precise contributions of intracellular chloride accumulation and extracellular potassium accumulation to depolarization remain unclear. Some experiments show substantial accumulation of intracellular chloride through the GABAA receptor which causes depolarization of the GABAA reversal potential (EGABA(A)) and may lead to GABA-mediated excitation [4,7] [8]. Other experiments show substantial extracellular potassium accumulation in GABA-mediated excitation [910] [5]. It is critical to distinguish how intracellular chloride accumulation and increases in extracellular potassium contribute to GABAAmediated excitation, since these levels are coupled through the primary chloride efflux mechanism, the potassium-chloride cotransporter, KCC2 [11] [7] [12] [5], which has been suggested as a potential therapeutic target to suppress pathological states in epilepsy and pain [13]. In order to understand how modulators of KCC2 activity should be used therapeutically, a clearer understanding of how potassium and chloride kinetics contribute to GABAA-mediated excitation is necessary. To determine ionic mechanisms of GABAA-mediated excitation we have developed a biophysically detailed computational model of a CA1 pyramidal cell that accounts for the myriad processes contributing to ionic homeostasis. To our knowledge, no computationally based morphological neuron model yet exists that incorporates both chloride and potassium homeostasis mechanisms to allow for simultaneous study of these essential coupled (via KCC2) ionic subsystems [11] [7] [12] [5]. An advantage of the computational approach that we employ is to allow for testing of assumptions about the electrophysiological and ionic activity in dendrites that are generally based on recordings from the soma. Additionally, experimental factors that may lead to conflicting interpretations of experimental data, such as off-target effects by pharmacological agents, can be explicitly controlled in the computational model. The model that we present suggests plausible ionic mechanisms of GABAA-mediated excitation and represents a foundation for future studies to investigate other disease mechanisms stemming from disruptions in ion homeostasis. The model may also be spatially extended to networks that can be used to investigate how GABAA-mediated depolarization in pyramidal cells triggers and supports sustained epileptiform activity in hippocampal circuits. Model Reco (...truncated)