Seizures emanating from the limbic system propagate and generalize via specific anatomic paths, which also involve the basal ganglia. They are a group of subcortical nuclei that physiologically convey mainly motor, but also cognitive and limbic functions (Bolam et al., 2000; DeLong and Wichmann, 2007; Al-Otaibi et al., 2011). Basal ganglia regions are part of the epileptic network and thus have been shown to be subject to plastic network changes upon repeated seizure activity (Gernert et al., 2004; Nolte et al., 2006; Kücker et al., 2010).
Furthermore, they have been reported to be involved in mechanisms of pharmacoresistance (Töllner et al., 2011). The basal ganglia include the substantia nigra (consisting of pars compacta and pars reticulata), the striatum (consisting of the nucleus caudatus and
putamen), the globus pallidus (rat; globus pallidus externus in humans), the entopeduncular nucleus (rat; globus pallidus internus in humans), and the STN. The basal ganglia regions are anatomically and functionally connected with each other and with the limbic system (Fig. 1).
Dysfunctions of the basal ganglia can lead to neuropsychiatric symptoms, cognitive changes, and hypo- or hyperkinetic movement disorders. The most common symptoms can be seen in Morbus Parkinson (tremor, bradykinesia, rigor, and bent body posture) and Chorea Huntington (extensive, involuntary movements) (DeLong, 2000). Physiologically, the basal ganglia have a gating function, meaning that they channel wanted movements and inhibit involuntary activities.
The basal ganglia network consists of parallel loops, which go from the cortex over the basal ganglia to the brain stem and the thalamus and from there back to the cortex. In temporal lobe epilepsies, seizures emanate from a focus within the temporal lobe (usually the hippocampus, the entorhinal cortex, or the amygdala). During secondary generalization (Fig.
1), seizure activity is transmitted from the focus via different routes to the basal ganglia, for example over the cortex to the striatum, which is considered as the entry gate of the basal ganglia network. The seizure propagation continues from the striatum to the SNr via a direct or indirect path. The direct striato-nigral projection is monosynaptic and utilizes the inhibitory neurotransmitter GABA. The activity of GABAergic striatal projection neurons (medium-sized spiny neurons) therefore results in an increased concentration of GABA in the SNr, which leads to an inhibition of nigral neurons (Hattori et al., 1973; Fonnum et al., 1978;
Bolam et al., 2000; Gale et al., 2008).
In contrast, the indirect striato-nigral path consists of three interconnections. The striatum innervates the globus pallidus (externus) via GABAergic projection neurons (medium-sized spiny neurons). From there, activity is transmitted again via GABAergic projections to the STN. The projection neurons of the STN innervate the SNr and lead to an increased activity of nigral neurons due to the release of the excitatory neurotransmitter glutamate. The STN is additionally regulated by further efferences such as from the cortex and the pedunculopontine nucleus (Alexander and Crutcher, 1990; Robledo and Feger, 1990; Bolam et al., 2000; Shen and Johnson, 2006; DeLong and Wichmann, 2007; Deniau et al., 2007; Gale et al., 2008).
Together with the entopeduncular nucleus, the SNr serves as an output gate of the basal ganglia. The SNr consists to 90% of GABAergic neurons and forwards information to different regions including thalamus, rostral colliculus (colliculus superior in humans), and pedunculopontine nucleus (Fonnum et al., 1978; Alexander and Crutcher, 1990; Bolam et al., 2000; Gale et al., 2008). The SNr is one of the best-studied basal ganglia structures with regard to its function in propagation and modulation of seizures. Moreover, it is a well-investigated basal ganglia target for experimental, therapeutic manipulations in epilepsy research (Iadarola and Gale, 1982; Garcia-Cairasco and Sabbatini, 1983; Le Gal La Salle et al., 1983; McNamara et al., 1984; De Sarro et al., 1991; Moshé et al., 1992; Depaulis et al., 1994;
Gernert and Löscher, 2001; Gale et al., 2008; Löscher et al., 2008; Nolte et al., 2008;
Thompson, 2009; Bröer et al., 2012). Due to reciprocal connections of basal ganglia and thalamus with the limbic system (Fig. 1), a direct modulation of seizure initiation in the limbic system can be achieved (Löscher et al., 2008).
Fig. 1: Schematic illustration of focal (limbic) and secondary generalized seizure propagation pathways in temporal lobe epilepsy.Emanating from the focus, which is located within the limbic system (light pink), seizures propagate via the cortex (blue), the basal ganglia (yellow), and their downstream structures (green). Several transmitters including γ-aminobutyric acid (GABA; red arrows) and glutamate (blue arrows) are involved in that epileptic network. Modified from Löscher et al., 2008
It is assumed that an increased inhibition of the SNr leads to a disinhibition of downstream structures and thereby prevents the generalization of epileptic seizures and, via the reciprocal connections with the limbic system, raises the threshold for seizure induction. This can be achieved by a direct inhibition of the SNr or indirectly via reduction of excitatory input from the STN. This principle of seizure reduction due to an increased direct inhibition of the SNr (Iadarola and Gale, 1982; McNamara et al., 1984; Dybdal and Gale, 2000; Bröer et al., 2012) or an indirect inhibition of the SNr by inhibiting the STN (Deransart et al., 1996;
Velísková et al., 1996; Deransart et al., 1998; Dybdal and Gale, 2000; Bröer et al., 2012) has been repeatedly used in local pharmacological or electrical modulations of the epileptic network. Even though this approach was also used for transplantation of inhibitory cells into the SNr (Löscher et al., 1998; Castillo et al., 2008; Löscher et al., 2008; Nolte et al., 2008;
Thompson et al., 2009), the STN has not been targeted for neurotransplantation studies so far (Fig. 3, Page 17).