Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Abstract

We showed that when CA3 pyramidal neurons in the caudal 80% of the dorsal hippocampus had almost disappeared completely, the efferent pathway of CA3 was rarely detectable. We used the mouse pilocarpine model of temporal lobe epilepsy (TLE), and injected iontophoretically the anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into gliotic CA3, medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei, or the retrograde tracer cholera toxin B subunit (CTB) into gliotic CA3 area of hippocampus. In the afferent pathway, the number of neurons projecting to CA3 from medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei increased significantly. In the hippocampus, where CA3 pyramidal neurons were partially lost, calbindin, calretinin, parvalbumin immunopositive back-projection neurons from CA1-CA3 area were observed. Sprouting of Schaffer collaterals with increased number of large boutons in both sides of CA1 area, particularly in the stratum pyramidale, was found. When CA3 pyramidal neurons in caudal 80% of the dorsal hippocampus have almost disappeared completely, surviving CA3 neurons in the rostral 20% of the dorsal hippocampus may play an important role in transmitting hyperactivity of granule cells to surviving CA1 neurons or to dorsal part of the lateral septum. We concluded that reorganization of CA3 area with its downstream or upstream nuclei may be involved in the occurrence of epilepsy.

Morpho‐Physiologic Characteristics of Dorsal Subicular Network in Mice after Pilocarpine‐Induced Status Epilepticus

“…Status epilepticus (SE) was induced according to our established procedures (28, 29, 53–56). Briefly, mice were given a single subcutaneous injection of methyl-scopolamine nitrate (1mg/kg) 30 min before the injection of either saline in the control or pilocarpine in the experimental groups.…”

“…Neuronal loss and synaptic reorganization of intra- and extra-hippocampal connections have been well-known to be associated with temporal lobe epilepsy (TLE) (3, 4, 6, 7, 9, 14, 17, 18, 27, 29, 33, 55, 56). As a major output of the hippocampus and the first brain region encountered by neural activity emanating from the hippocampus (1, 41, 42), subiculum is also found to play an important role in the initiation and maintenance of epileptic discharges in TLE (5, 16).…”

Cytoarchitectonics and afferent/efferent reorganization of neurons in layers II and III of the lateral entorhinal cortex in the mouse pilocarpine model of temporal lobe epilepsy

“…It receives dual afferent inputs from CA1 pyramidal neurons and from layer II/III of the entorhinal cortex in normal humans and animals. However, loss of CA1 and CA3 pyramidal neurons in patients with intractable TLE (Tang et al, 2001; Tang and Lee, 2001) and in the mouse model of TLE (Tang et al, 2005, 2006; Ma et al, 2006) makes it possible that the entorhinal cortex–subiculum pathway plays a crucial role in subiculum‐related initiation and maintenance of epileptic discharges. The presence of sprouted axons and enlarged PHA‐L‐immunopositive en passant and terminal boutons in the subiculum in the present study may an provide neuroanatomical basis to support the enhancement of interaction between LEnt and subiculum, leading to epileptic firing in the subiculum that was shown in our recent in vivo single‐cell recording (unpublished data).…”

“…Male Swiss mice weighing 25–30 g were used according to our established procedures (Tang et al, 2005, 2006; Ma et al, 2006). Mice were given a single subcutaneous injection of methylscopolamine nitrate (1 mg/kg) 30 min before the injection of either saline in the control or pilocarpine in the experimental mice.…”

“…Disinhibited entorhinal neurons evoke ictal discharges, which activate granule cells through perforant pathway and CA1 pyramidal neurons by the temporoammonic pathway, and the latter reenter the entorhinal cortex directly or through the subiculum (Kloosterman et al, 2003), forming an entorhinal cortex–hippocampus–entorhinal cortex loop, and facilitate the initiation of self‐sustained epileptiform activity (Pare et al, 1992; Kumar and Buskmaster, 2006). However, the reported hyperinhibition of granule cells (Buckmaster and Dudek, 1997; Wu and Leung, 2001; Sloviter et al, 2006) and loss of CA1 and CA3 pyramidal neurons, which disrupts trisynaptic neural pathway in the hippocampus in this animal model of TLE (Tang et al, 2005, 2006; Ma et al, 2006), have sparked debate on whether perforant and/or temporoammonic pathways are involved in the occurrence of TLE. We therefore hypothesize that, in addition to the perforant pathway, reorganization of other efferent and afferent pathways of the entorhinal cortex may be involved in epileptogenesis.…”