Recent evidence indicates that long-chain polyunsaturated fatty acids (PUFAs) can prevent cardiac arrhythmias by a reduction of cardiomyocyte excitability. This was shown to be due to a modulation of the voltage-dependent inactivation of both sodium (INa) and calcium (ICa) currents. To establish whether PUFAs also regulate neuronal excitability, the effects of PUFAs on INa and ICa were assessed in CAl neurons freshly isolated from the rat hippocampus. Extracellular application of PUFAs produced a concentrationdependent shift of the voltage dependence of inactivation of both INa and ICa to more hyperpolarized potentials. Consequently, they accelerated the inactivation and retarded the recovery from inactivation. The EC50 for the shift of the INa steady-state inactivation curve was 2.1 + 0.4 ,uM for docosahexaenoic acid (DHA) and 4 + 0.4 ,uM for eicosapentaenoic acid (EPA). The EC50 for the shift on the ICa inactivation curve was 2.1 + 0.4 for DHA and >15 ,uM for EPA. Additionally, DHA
In the hippocampus, the calcium-binding protein parvalbumin (PV) is expressed in interneurons that innervate perisomatic regions. PV in GABAergic synaptic terminals was proposed to limit repetitive GABA release by buffering of "residual calcium." We assessed the role of presynaptic PV in Ca(2+)-dependent GABA release in the hippocampus of PV-deficient (PV-/-) mice and wild-type (PV+/+) littermates. Pharmacologically isolated inhibitory postsynaptic currents (IPSCs) were evoked by low-intensity stimulation of the stratum pyramidale and recorded from voltage-clamped CA1 pyramidal neurons. The amplitude and decay time constant of single IPSCs were similar for both genotypes. Under our experimental conditions of reduced release probability and minimal presynaptic suppression, paired-pulse facilitation of IPSCs occurred at intervals from 2 to 50 ms, irrespective of the presence of PV. The facilitation of IPSCs induced by trains of 10 stimuli at frequencies >20 Hz was enhanced in cells from PV-/- mice, the largest difference between PV-/- and PV+/+ animals (220%) being observed at 33 Hz. The effect of IPSC facilitation at sustained gamma frequencies was assessed on kainate-induced rhythmic IPSC-paced neuronal oscillations at gamma frequencies, recorded with dual field potential recordings in area CA3. The maximum power of the oscillation was 138 microV(2) at 36 Hz in slices from PV+/+ mice and was trebled in slices from PV-/- mice. PV deficiency caused a similar increase in gamma power under conditions used to study IPSC facilitation and can be explained by an increased facilitation of GABA release at sustained high frequencies. The dominant frequency and coherence were not affected by PV deficiency. These observations suggest that PV deficiency, due to an increased short-term facilitation of GABA release, enhances inhibition by high-frequency burst-firing PV-expressing interneurons and may affect the higher cognitive functions associated with gamma oscillations.
How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (Ͼ100 Hz) and reduction in system complexity. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are generated by the near-synchronous (within ϳ5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is characterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure.
Networks of GABAergic interneurons are of utmost importance in generating and promoting synchronous activity and are involved in producing coherent oscillations. These neurons are characterized by their fast-spiking rate and by the expression of the Ca 2+ -binding protein parvalbumin (PV). Alteration of their inhibitory activity has been proposed as a major mechanism leading to epileptic seizures and thus the role of PV in maintaining the stability of neuronal networks was assessed in knockout (PVÀ/À) mice. Pentylenetetrazole induced generalized tonic -clonic seizures in all genotypes, but the severity of seizures was significantly greater in PVÀ/À than in PV+/+ animals. Extracellular single-unit activity recorded from over 1000 neurons in vivo in the temporal cortex revealed an increase of units firing regularly and a decrease of cells firing in bursts. In the hippocampus, PV deficiency facilitated the GABA A ergic current reversal induced by high-frequency stimulation, a mechanism implied in the generation of epileptic activity. We postulate that PV plays a key role in the regulation of local inhibitory effects exerted by GABAergic interneurons on pyramidal neurons. Through an increase in inhibition, the absence of PV facilitates synchronous activity in the cortex and facilitates hypersynchrony through the depolarizing action of GABA in the hippocampus.
The cellular and network mechanisms of the transition of brief interictal discharges to prolonged seizures are a crucial issue in epilepsy. Here we used hippocampal slices exposed to ACSF containing 0 Mg 2ϩ to explore mechanisms for the transition to prolonged (3-42 sec) seizure-like ("ictal") discharges. Epileptiform activity, evoked by Shaffer collateral stimulation, triggered prolonged bursts in CA1, in 50-60% of slices, from both adult and young (postnatal day 13-21) rats. In these cases the first component of the CA1 epileptiform burst was followed by a train of population spikes at frequencies in the ␥ band and above (30-120 Hz, reminiscent of tetanically evoked ␥ oscillations). The ␥ burst in turn could be followed by slower repetitive "tertiary" bursts. Intracellular recordings from CA1 during the ␥ phase revealed long depolarizations, action potentials rising from brief apparent hyperpolarizations, and a drop of input resistance. The CA1 ␥ rhythm was completely blocked by bicuculline (10-50 M), by ethoxyzolamide (100 M), and strongly attenuated in hyperosmolar perfusate (50 mM sucrose). Subsequent tertiary bursts were also blocked by bicuculline, ethoxyzolamide, and in hyperosmolar perfusate. In all these cases intracellular recordings from CA3 revealed only short depolarizations. We conclude that under epileptogenic conditions, ␥ band oscillations arise from GABA A ergic depolarizations and that this activity may lead to the generation of ictal discharges.Key words: depolarizing GABA response; neuronal synchronization; ␥ rhythms; ictogenesis; epilepsy models; hippocampus Cellular and network mechanisms of epileptiform discharges lasting a few hundred milliseconds, resembling interictal discharges, are understood in detail, largely because of experiments in vitro (Traub and Wong, 1982;Hablitz, 1987;Mody et al., 1987;Tancredi et al., 1990;Köhling et al., 1994;Gloveli et al., 1995). In the hippocampus they result from the interplay of intrinsic currents and synaptic interconnections in CA3 (Traub and Wong, 1982;Miles and Wong, 1986;Traub et al., 1994Traub et al., , 1996a. Prolonged seizure-like (Ͼ2 sec; ictal) activity rarely occurs in adult slices (Anderson et al., 1986;Rafiq et al., 1993;Stasheff et al., 1993a;Traub et al., 1996a;Borck and Jefferys, 1999), but more often in juvenile tissue (Hablitz, 1987;Swann et al., 1993;Gloveli et al., 1995). Most reports on ictal activity in slices implicate prolonged, glutamatergic depolarizations variously depending on NMDA receptors [0 Mg 2ϩ and electrographic "seizures" (Rafiq et al., 1993;Stasheff et al., 1993b;Traub et al., 1994)], AMPA receptors [4-aminopyridine (Traub et al., 1995)], or combined AMPA, NMDA and metabotropic glutamate receptors (mGluRs) [GABA A antagonists (Swann et al., 1993;Traub et al., 1996a;Merlin, 1999;Borck and Jefferys, 1999)].Epileptic activity is often attributed to imbalanced glutamatergic excitation and GABAergic inhibition. However, GABAergic transmission remains effective in some epilepsy models and in epileptogenic human tissue...
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