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The mechanism of abrupt transition between theta and hyper-excitable spiking activity in medial entorhinal cortex layer II stellate cells.

ABSTRACT: Recent studies have shown that stellate cells (SCs) of the medial entorhinal cortex become hyper-excitable in animal models of temporal lobe epilepsy. These studies have also demonstrated the existence of recurrent connections among SCs, reduced levels of recurrent inhibition in epileptic networks as compared to control ones, and comparable levels of recurrent excitation among SCs in both network types. In this work, we investigate the biophysical and dynamic mechanism of generation of the fast time scale corresponding to hyper-excitable firing and the transition between theta and fast firing frequency activity in SCs. We show that recurrently connected minimal networks of SCs exhibit abrupt, threshold-like transition between theta and hyper-excitable firing frequencies as the result of small changes in the maximal synaptic (AMPAergic) conductance. The threshold required for this transition is modulated by synaptic inhibition. Similar abrupt transition between firing frequency regimes can be observed in single, self-coupled SCs, which represent a network of recurrently coupled neurons synchronized in phase, but not in synaptically isolated SCs as the result of changes in the levels of the tonic drive. Using dynamical systems tools (phase-space analysis), we explain the dynamic mechanism underlying the genesis of the fast time scale and the abrupt transition between firing frequency regimes, their dependence on the intrinsic SC's currents and synaptic excitation. This abrupt transition is mechanistically different from others observed in similar networks with different cell types. Most notably, there is no bistability involved. 'In vitro' experiments using single SCs self-coupled with dynamic clamp show the abrupt transition between firing frequency regimes, and demonstrate that our theoretical predictions are not an artifact of the model. In addition, these experiments show that high-frequency firing is burst-like with a duration modulated by an M-current.

SUBMITTER: Kispersky T

PROVIDER: S-EPMC2973955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The adenosinergic system is known to exert an inhibitory affect in the brain, and as such adenosine has been considered an endogenous anticonvulsant. Entorhinal cortex (EC) layer II neurons, which serve as the primary input to the hippocampus, are spared in temporal lobe epilepsy (TLE) and become hyperexcitable. Because these neurons also express adenosine receptors, the activity of these neurons may be controlled by adenosine, specifically during seizure activity when adenosine levels are thought to rise. In light of this, we determined if the actions of adenosine on medial EC (mEC) layer II stellate neurons are augmented in TLE and by which receptor subtype.Horizontal brain slices were prepared from rats exhibiting spontaneous seizures (TLE) induced by electrical stimulation and compared with age-matched control rats. mEC layer II stellate neurons were visually identified, and action potentials (APs) were evoked either by a series of depolarizing current injection steps or via presynaptic stimulation of mEC deep layers. The effects of adenosine were compared with actions of adenosine A(1) and A(2A) receptor-specific agonists (CPA and CGS-21680) and antagonists (DPCPX and ZM-241385), respectively. Immunohistochemical and qPCR techniques were also employed to assess relative adenosine A(1)-receptor message and expression.mEC layer II stellate neurons were hyperexcitable in TLE, evoking a higher frequency of APs when depolarized and generating bursts of APs when synaptically stimulated. Adenosine reduced AP frequency and synaptically evoked APs in a dose-dependent manner (500 nM-100 ?M); however, in TLE, the inhibitory actions of adenosine occurred at concentrations that were without affect in control neurons. In both cases, the inhibitory actions of adenosine were mediated via activation of the A(1)- and not the A(2A)-receptor subtype. Quantitative polymerase chain reaction (qPCR) and immunohistochemical experiments revealed an upregulation of the adenosine A(1) mRNA and an increase in A(1)-receptor staining in TLE neurons compared to control.Our data indicate that the actions of adenosine on mEC layer II stellate neurons is accentuated in TLE due to an upregulation of adenosine A(1)-receptors. Because adenosine levels are thought to rise during seizure activity, activation of adenosine A(1)-receptors could provide a possible endogenous mechanism to suppress seizure activity and spread within the temporal lobe.

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The mechanism of abrupt transition between theta and hyper-excitable spiking activity in medial entorhinal cortex layer II stellate cells.

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