El consumo de drogas en la adolescencia desde la perspectiva del Trabajo Social

out. Seizure activity in vivo leads to a significant elevation of [K+]out (up to 10-12 mM) and high levels of [K+]out are

(Traynelis and Dingledine, 1988; reviewed in Somjen, 2002). Potassium buffering has been analyzed in numerous model systems identifying glial Na+/K+-ATPase and Kir channels as

important mediators of this astrocyte function (reviewed in Potassium Spatial Buffering by Astrocytes, page 46). Interestingly, a reduction of astrocyte Kir current was consistently seen

in different epilepsy models in situ and in human epileptic tissue (Bordey et al., 2000, 2001;

D’Ambrosio et al., 1999; Francke et al., 1997; Schroder et al., 1999). For example, in the pilocarpine seizure model, effects of Ba2+ on stimulus induced changes in [K+]out suggested a

significant reduction of Kir current in astrocytes in the CA1 hippocampal area of epileptic

rats (Gabriel et al., 1998). These findings were in agreement with experiments investigating hippocampal tissue obtained from patients with pharmaco-resistant temporal lobe epilepsy. An impaired regulation of [K+]out was noted in highly sclerotic CA1 region of patients with

Ammon’s horn sclerosis as compared to control non-sclerotic tissue (Gabriel et al., 1998; Kivi et al., 2000 ). A diminished astroglial Kir current was later found to be present as well

(Jauch et al., 2002; Bordey and Sontheimer, 1998; Hinterkeuser et al., 2000). It has been suggested that post-traumatic intracellular accumulation of Na+ and Cl- may decrease the

membrane K+ _{conductance by blocking K}+ _{channels (Harvey and Ten Eick, 1989; Bekar and}

Walz, 2002; Orikabe et al., 2003). Indeed, excess accumulation of intracellular Na+ can

decrease both outwardly rectifying and inwardly rectifying membrane currents in astrocytes (Jabs et al., 1994; Schroder et al., 2002). Such current decrease was observed in post- traumatic CA3 astrocytes in situ (D’Ambrosio et al., 1999). In addition, it was suspected that

brain injury, by inducing glial cells to divide and move towards the injured site, requires their dedifferentiation which leads to the decrease in Kir conductance. This hypothesis was

of inwardly rectifying K+ currents and gain more outwardly rectifying currents (MacFarlane

and Sontheimer, 1997; Bordey et al., 2001). It should also be noted that reduced Kir current

was found to accompany mitotic activity in astrocytes in lesion models both in vitro and in situ (MacFarlane and Sontheimer, 1997; Bordey et al., 2001). The question which of the

multiple Kir subunits are affected in sclerosis to reduce inward rectification and K+ buffering

still has to be answered, although preliminary data identified Kir4.1 as a potential candidate

(Seifert et al., 2002). In support, recent genetic linkage studies have identified an association between missense variations in the gene encoding the Kir4.1 potassium channel (KCNJ10)

and seizure susceptibility phenotypes in both humans and mice (Lenzen et al., 2005; Buono et al., 2004; Ferraro et al., 2004). Interestingly, the Na+/K+-ATPase α2 subunit (ATP1A2)

gene was also implicated in seizure susceptibility (Ferraro et al., 1999), however a recent study has shown that no association can be found between common variations in the human ATP1A2 gene and idiopathic generalized epilepsy (Luhoff et al., 2005). It remains unclear whether channel dysfunction, increased astrocyte proliferation, or dedifferentiation of formerly mature cells constitutes the basis for the observed loss of astroglial Kir current in

epileptic tissue.

Glial Na+ and Ca2+ channels may also play a role in epileptogenesis. Previous work in

cell culture and in situ suggests that astrocytes and neurons share a common set of voltage-

gated Na+ channels including Nav1.1-1.3, 1.5 and 1.6 (Black et al., 1994, 1998; Oh et al.,

1994; Schaller et al., 1995). Although the physiological role of glial Na+ channels is not well

understood, it has been proposed that they might regulate [Na+_]

out and thereby control the

activity of Na+-dependent transporters such as the glutamate transporters and Na+/K+-

sclerotic and epileptic CNS. A dramatic upregulation was seen in cultured astrocytes isolated from the seizure focus of human epileptic tissue. The cells possessed depolarized resting membrane potentials and were even capable of generating action potential-like responses upon current injection (O’Connor et al., 1998; Bordey and Sontheimer, 1998a,b). These data suggested that astrocytes overexpressing Na+ channels might support spread of seizure

activity. Similar overexpression of Na+ channels in the reactive astrocytes and the capacity to

sustain slow-action potentials was also observed in acute biopsies from human epileptic hippocampus (Bordey and Sontheimer, 1998b), but not in the hippocampal brain slices obtained from human temporal lobe epilepsy patients (Hinterkeuser et al., 2000). Further studies are therefore required to establish a clear role of astrocyte Na+ channels in the

epileptic tissue.

Voltage-gated Ca2+ channels mediate Ca2+ influx upon membrane depolarization and

regulate various intracellular processes in excitable and non-excitable cells. During seizure activity [Ca2+]out decreases at the focus site (Heinemann et al., 1977). In acute hippocampal

slices, low [Ca2+]out leads to spontaneous seizure-like neuronal discharge patterns implicating

a role for Ca2+ _{in the generation of epileptic activity}

in vivo (Haas and Jefferys, 1984;

Konnerth et al., 1986). Although the seizure-induced decrease in [Ca2+]out is usually

attributed to Ca2+ influx into neurons, different types of Ca2+ channels have been identified in

astrocytes and may contribute to [Ca2+]out depletion (Verkhratsky and Steinhäuser, 2000). In

favor of this hypothesis, immunostaining noted an upregulation of astrocytic L-type Ca2+

channels in the kainite model of epilepsy (Westenbroek et al., 1998). In addition, Ca2+ _influx

growth factors, thereby indirectly influencing the architecture and activity of neural circuitry (Steinhäuser and Seifert, 2002).

In conclusion, evidence showing reduced astroglial Kir current and increased Na+ and

Ca2+ conductance in sclerotic epileptic tissue is accumulating. These alterations in

conjunction with the seizure induced shrinkage of the extracellular space may lead to impaired spatial buffering, resulting in strong and prolonged depolarization of glial cells and neurons in response to activity-dependent release of K+. Thus, modified properties of

astrocytes might directly contribute to or even initiate seizure generation and seizure spread in hippocampal sclerosis (reviewed in Steinhäuser and Seifert, 2002). In addition, the role of oligodendrocytes in the overall extracellular K+ homeostasis should also not be neglected

since recent work has demonstrated that this type of macroglia is suitable for K+ uptake that

may be reduced under certain pathological conditions (Chvatal et al., 1997, 1999; D’Ambrosio et al., 1999).