Abstract
A critical property of some neurons is burst firing, which in the hippocampus plays a primary role in reliable transmission of electrical signals. However, bursting may also contribute to synchronization of electrical activity in networks of neurons, a hallmark of epilepsy. Understanding the ionic mechanisms of bursting in a single neuron, and how mutations associated with epilepsy modify these mechanisms, is an important building block for understanding the emergent network behaviors. We present a single-compartment model of a CA3 hippocampal pyramidal neuron based on recent experimental data. We then use the model to determine the roles of primary depolarizing currents in burst generation. The single compartment model incorporates accurate representations of sodium (Na+) channels (NaV1.1) and T-type calcium (Ca2+) channel subtypes (CaV3.1, CaV3.2, and CaV3.3). Our simulations predict the importance of Na+ and T-type Ca2+ channels in hippocampal pyramidal cell bursting and reveal the distinct contribution of each subtype to burst morphology. We also performed fast-slow analysis in a reduced comparable model, which shows that our model burst is generated as a result of the interaction of two slow variables, the T-type Ca2+ channel activation gate and the Ca2+-dependent potassium (K+) channel activation gate. The model reproduces a range of experimentally observed phenomena including afterdepolarizing potentials, spike widening at the end of the burst, and rebound. Finally, we use the model to simulate the effects of two epilepsy-linked mutations: R1648H in NaV1.1 and C456S in CaV3.2, both of which result in increased cellular excitability.
Highlights
A hallmark of CA3 hippocampal neurons is intrinsic burst firing
The cellular epileptic waveform resulting from synaptic interactions is the paroxysmal depolarizing shift (PDS), a waveform that is distinct from the endogenous single cell burst mediated by the active membrane properties in an individual cell [5]
We focused on three types of low-voltage-activated T-type Ca2+ channels that were recently identified in CA3 neurons [28], since they have been implicated in afterdepolarizing potential (ADP) generation in Purkinje and thalamic relay neurons [29]
Summary
A hallmark of CA3 hippocampal neurons is intrinsic burst firing. In primates 95% of CA3 neurons burst [1], while in rodents distinct populations of bursting and non-bursting CA3 neurons have been identified [2]. The endogenous cellular burst and the network burst In a network of neurons synchronous bursting causes seizures [4], a hallmark of epilepsy. Unlike an endogenous burst in a single neuron, synchronous bursting in a population depends on synaptic interactions between neurons. The cellular epileptic waveform resulting from synaptic interactions is the paroxysmal depolarizing shift (PDS), a waveform that is distinct from the endogenous single cell burst mediated by the active membrane properties in an individual cell [5]. Network bursts and endogenous bursts are associated; the propensity of CA3 neurons to fire bursts of four to five action potentials may increase 10-fold the probability of recruiting synaptically connected neurons to burst [5], and the synaptic integration required for network transmission is mediated by active conductances in the membrane. Understanding the ionic mechanisms of CA3 bursting is important to determine the mechanisms of synchronized behavior in neuronal networks
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