Reorganization of the septohippocampal cholinergic fiber system in experimental epilepsy

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Temporal lobe epilepsy (TLE), the most common form of focal epilepsy, can be associated with morphological changes in the hippocampal formation (HF), which include progressive neuron loss and gliosis (Curia et al., 2014; Engel, 1996). Given the involvement of the HF in the mediation of cognition and emotion, it is not surprising that TLE patients frequently show learning deficits (Alessio et al., 2004), anxiety (Piazzini, Canevini, Maggiori, & Canger, 2001), and mood disorders (Gaitatzis, Trimble, & Sander, 2004). However, the etiological mechanisms underlying TLE and its comorbid disorders are not fully understood. It has been suggested that recurrent excitation of the granule cells of the dentate gyrus due to aberrant sprouting of their axon collaterals (mossy fiber sprouting) can render hippocampal circuits hyperexcitable and, therefore, epileptogenic (Cronin, Obenaus, Houser, & Dudek, 1992; Tauck & Nadler, 1985; Zeng, Rensing, & Wong, 2009). The results of recent studies showed, however, that spontaneous seizures, at least in experimental animals, can precede mossy fiber sprouting (Bumanglag & Sloviter, 2008) and that blockade of synaptogenesis with rapamycin does not affect seizure frequency (Buckmaster & Lew, 2011; Yamawaki, Thind, & Buckmaster, 2015). Thus, the potential involvement of other cellular and molecular mechanisms in epileptogenesis should be considered. In particular, an increasing body of evidence indicates that changes in peptidergic (Kovac & Walker, 2013), monoaminergic (Bagdy, Kecskemeti, Riba, & Jakus, 2007), and cholinergic (Friedman, Behrens, & Heinemann, 2007) neurotransmission may be also implicated in epilepsy.
The cell bodies of cholinergic neurons innervating the HF are located in the medial septum and vertical limb of the diagonal band of Broca (MS/DB) (Mesulam, Mufson, Wainer, & Levey, 1983). The axons of these cells possess numerous specialized vesicle‐filled swellings or varicosities capable of releasing acetylcholine into the synaptic cleft or the extracellular space (Turrini et al., 2001) where it can bind to its neuronal and astroglial receptors (Drever, Riedel, & Platt, 2011; Pabst et al., 2016). Although the functional roles of this septohippocampal cholinergic pathway are not yet fully established, there is strong evidence for its involvement in hippocampal physiology, including the maintenance of rhythmic activity of hippocampal neurons (Buzsaki, 2002; Dannenberg et al., 2015) and cognitive functions (Berger‐Sweeney et al., 2001; Teles‐Grilo Ruivo & Mellor, 2013). In addition, several lines of evidence show that changes in cholinergic neurotransmission can be also involved in hippocampal epileptogenesis. For example, both systemic (Turski et al., 1983) and focal (D'Antuono et al., 2007; Lindekens et al., 2000; Nagao, Alonso, & Avoli, 1996) applications of cholinergic agonists are known to induce seizure activity in hippocampal networks, which can then progress to a chronic state (Leite, Garcia‐Cairasco, & Cavalheiro, 2002). Furthermore, stimulation of the medial septum and intraseptal infusions of GABAergic or cholinergic agents alter hippocampal seizure threshold (Kichigina, Butuzova, & Sinel'nikova, 2007; Miller, Turner, & Gray, 1994), whereas immunotoxic lesions of septal cholinergic cells increase seizure susceptibility (Ferencz et al., 2001; Silveira, Cha, & Holmes, 2002) and exacerbate seizure‐induced neuron loss in the hilus of the dentate gyrus (Jolkkonen, Kahkonen, & Pitkanen, 1997).
Despite the existence of indisputable evidence regarding the involvement of cholinergic neurotransmission in epilepsy, very little is known about the structural features of the septohippocampal projection system in epileptic brain. Prior studies showed that epileptic seizures in laboratory animals can be associated with the sprouting of fibers immunoreactive to acetylcholinesterase (Holtzman & Lowenstein, 1995) and with both atrophic (Correia, Amado, Cavalheiro, & Bentivoglio, 1998) and hypertrophic (Holtzman & Lowenstein, 1995) morphological alterations in the MS cholinergic cells.

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