Eiichi Maru

Functional and Morphological Changes in the Hippocampal Neuronal Circuits Associated with Epileptic Seizures

Summary:  Purpose: We review what is currently known about functional and morphologic plasticity of hippocampal neuronal circuits in animal epilepsy models.

Vagus nerve stimulation induced long-lasting enhancement of synaptic transmission and decreased granule cell discharge in the hippocampal dentate gyrus of urethane-anesthetized rats

Vagus nerve stimulation (VNS) ameliorates deficits of hippocampal functions, such as contextual learning and memory, probably through direct modulation of neuronal activity. Previous studies showed that VNS enhanced excitatory synaptic transmission in the hippocampal CA3 area via activation of β-adrenergic receptors. However, effects of VNS on excitatory synaptic transmission and action potential (AP) discharge of granule cells (GCs) in the dentate gyrus have not been studied. Urethane-anesthetized rats were used to investigate whether VNS influences synaptic transmission efficacy at perforant path-GC synapses and population spike discharge in the dentate gyrus. Intermittent burst stimulation of the left vagus nerve (30Hz for 30s at an inter-train interval of 5min for 1h) significantly enhanced the perforant path-GC synaptic transmission efficacy in the dentate gyrus for at least 2h, indicating that VNS can induce a long-lasting enhancement of synaptic transmission in this area, similar to the situation observed in the CA3 area. In contrast, a 60-min period of VNS significantly reduced population spike amplitude (a parameter reflecting synchronized AP discharge of GCs) for a given excitatory postsynaptic potential. These findings suggest that acute VNS enhances the excitatory synaptic transmission and reduces synchronized AP discharge of GCs in the dentate gyrus. It is likely that enhancement of excitatory synaptic transmission and reduction of GC excitability contribute VNS treatment efficacy for learning deficits and intractable epilepsy, respectively.

Levetiracetam inhibits kindling-induced synaptic potentiation in the dentate gyrus of freely moving rats.

A novel antiepileptic drug, levetiracetam, strongly suppresses the development of kindling, although the mechanisms by which it does so are still unknown. Kindling-induced synaptic potentiation (KIP) is considered to play an important role in the development of kindling. Therefore, we examined the effect of levetiracetam on KIP during perforant path kindling in freely moving rats. Daily administration of levetiracetam significantly suppressed the development of kindling. Furthermore, levetiracetam significantly inhibited the development of KIP during 21 days of kindling. These results suggest that levetiracetam may suppress kindling development through the suppression of KIP.

Recurrent Excitation of Dentate Granule Cells in Kindled Rat During Self‐sustained Seizure Activity Probably Via Sprouted Mossy Fibers.

neurons. Moreover, the frequency of mEPSCs was increased. These results suggest that the augmentation of evoked EPSPs and EPSCs in kindled neurons is caused by facilitated glutamate (or aspartate or both) release from the nerve terminals. Considering the finding that the degree of the increase in the mEPSC amplitude in kindled neurons was less than that in the evoked EPSCs in kindled neurons, the enhancement of evoked EPSCs may be the result of increases in both the quantal size and quantal content of the synaptic vesicles. Alternatively, a new synaptic formation of the glutamatergic nerve terminals would be formed on the proximal dendrites in the kindled rat.

Lipid Peroxides and Neuronal Plasticity

Long-term potentiation (LTP) of synaptic transmission is a well defined form of neuronal plasticity. The induction of LTP at perforant path-dentate granule cell and Schaffer collateral-CA1 pyramidal cell synapses of the hippocampus is known to require influx of Ca2+ through postsynaptic N-methy1-D-aspartate (NMDA) receptors, while the expression of LTP has been proposed to be mediated at least in part through presynaptic1) Epileptic seizures which are associated with massive increases of intracellular cation concentration may also account for the persistent increases in efficacy of excitatory synaptic transmission in the hippocampus2) This seizure-induced synaptic potentiation (SIP) and LTP have some features in common such as the requirement of NMDA receptor activation1,3) and the consequent increase in neurotransmitter release4,5). These findings led to the concept of a retrograde messenger by which the presynaptic terminals are informed that the postsynaptic sites have been activated. Arachidonic acid (AA) has been recognized as the potential candidate for a retrograde messenger1). Here, we have addressed the involvement of lipid peroxides, especially lipoxygenase metabolites, in neuronal plasticity.

The angiotensin II type I receptor antagonist losartan retards amygdala kindling-induced epileptogenesis

Blood-brain barrier (BBB) breakdown and the subsequent exposure of the cerebral cortex to serum albumin are known to activate transforming growth factor β (TGF-β) signaling in astrocytes and to play key roles in epileptogenesis after brain injury. It was recently reported that the angiotensin II type I receptor antagonist losartan suppresses activation of TGF-β signaling and prevents epileptogenesis in a rat vascular injury model. Here, we investigated the effects of losartan on epileptogenesis following amygdala kindling in rats. Systemic or intracerebroventricular (i.c.v.) administration of losartan significantly delayed the development of severe behavioral seizures and stimulus-induced seizures on EEG (afterdischarge) in the early stage of amygdala kindling, as assessed by electroencephalography. Losartan also significantly increased the number of stimulations required to reach the fully kindled state. However, losartan had no effects on the threshold for afterdischarge induction, the afterdischarge duration, or seizure severity in fully kindled rats. Evaluation of BBB permeability by Evans blue staining did not indicate BBB breakdown (extravasation of serum albumin) in any region of the brain in the fully kindled animals. Thus, losartan may be useful in preventing epileptogenesis, even in post brain-insult epilepsy, in the absence of BBB breakdown.

1406 Peroxidized diacylglycerol enhances long-term potentiation of the rat hippocampal CA1 in vitro

1406 Peroxidized diacylglycerol enhances long-term potentiation of the rat hippocampal CA1 in vitro. MAKOTO NISHIYAMA, NOBUAKI HORI §, KEN11 SUZUKI&, TAKASHI WATANABE, TOMOKATSU HORI, SLJSUMU TAKEKOSHI

Inducible brain COX-2 facilitates the recurrence of hippocampal seizures in mouse rapid kindling

, KEIICHI WATANABE

Optical recording study of granule cell activities in the hippocampal dentate gyrus of kainate-treated rats.

, EIICHI MARU’, TAKAO SHIMIZU ll, and YORIHIRO YAMAMOTO”: Div. of Neurosur~., Inst. of Neurol. Scis., Tottori Univ. Sch. of Med., Yonago 683, p Dept. of Pharmacol., Kvushu Univ., Fat. of Dent., Fukuoka 812,

Kindling induced mossy fiber sprouting has no functional significance in developing seizure discharges in rats

Dept. of Pathol., Sch. of Med., Tokai Univ., Isehara 259-ll,&Dept. of Phvsiol., Nippon Med. Sch., Tokyo l& n Dept. of Biochem., Fat. of Med., Univ. of Tokyo, Tokyo 113, *Res. Center of Adv. Sci. and Technol., Univ. of Tokyo, Tokyo 115, lapan. It is possibility that protein kinase C (PKC) is associated with the expression of the long-term potentiation (LTP) and the generation of delayed neuronal cell death in rat hippocampal CA1 area. We had electrophysiologically examined the efficacy of a novel biological PKC activator, lipid-peroxidized diacylglycerol (DAGOOH), which had an equivalent potency to a phorbol ester (PMA) in the hippocampal slice preparations. We focused on the correlation between LTP in CA1 and the sensitivity of postsynaptic membrane to ionotophoretic application of non-NMDA and NMDA ligands. LTP was remarkably augmented by DAGOOH (500 nM), as compared with diacylglycerol(500 nM) and PMA (500 r&I). The magnitude of LTP showed oscillatory fluctuations in independent of postsynaptic chemo-sensitivity with pretreatment of DAGOOH. These results suggest that DAGOOH may activate the PKC both in the preand post-synaptic membrane.