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    • br Pathological consequences of disruption in the

    2022-09-27


    Pathological consequences of disruption in the GABA/T current equilibrium This issue has been particularly investigated in the context of absence seizures. These seizures are non-convulsive epileptic attacks present in many generalized genetic epilepsies that are characterized by a sudden and relatively brief impairment of consciousness, invariably accompanied by generalized and synchronous 2.5–4 Hz spike-and-waves discharges in human EEG (Crunelli and Leresche, 2002). On the basis of the in vitro experiments performed in ferret thalamic slices, McCormick and his colleagues proposed that the recruitment of GABAB IPSPs due to a pathologically strong corticothalamic input, and their associated potent rebound LTSs, underlies absence seizure generation (Blumenfeld and McCormick, 2000) (see also (Bal et al., 2000)). While in vivo recordings in cat and rat models of absence epilepsy have so far failed to report the presence of GABAB IPSPs followed by rebound LTS in TC Bufalin during seizures, they nevertheless show rhythmic sequences of composite GABAA IPSPs which occur in synchrony with each spike and wave complex (Pinault et al., 1998, Steriade and Contreras, 1995). This suggests that the rhythmic occurrence of GABA IPSPs that frame the thalamic output is a fundamental component of the mechanism that lead to the generation of this pathological rhythm. In addition, tonic GABAA inhibition is increased in almost all rodent models of absence epilepsy (Cope et al., 2009) and, in the best established pharmacological model of absence epilepsy, the GHB model, the pathological rhythmic activity relies on the activation of GABAB receptors (Venzi et al., 2015). Whatever the receptor type involved, the high level of GABA inhibition present in TC neurons during spike-and-waves discharges is sustained by robust LTSs in NRT neurons at each spike and wave complex, as observed in fentanyl-anesthetized rat model of absence epilepsy (Slaght et al., 2002). In agreement with the importance of LTSs in NRT neurons, an increased T-current was observed in these neurons in absence epilepsy-prone compared to non-epileptic rats (Tsakiridou et al., 1995). In summary, although the precise cellular mechanisms are still debated, numerous evidences point to the importance of both GABA inhibitory tonus and T-current activation in the pathogenesis of absence epilepsy. Interestingly, the pathogenicity of an impaired balance between thalamic T-channels and GABA receptors is now considered in a larger context than absence epilepsy. Indeed, an increasing number of clinical studies have reported the presence of slower theta thalamocortical oscillations in awake patients who present a wide variety of neurological and psychiatric conditions, including neurogenic pain, tinnitus and Parkinson's disease (Jeanmonod et al., 1996, Llinas et al., 1999, Steriade et al., 1993). While the mechanisms of such dysrhythmia are still to be explored, a common principle has been proposed implying an increase inhibitory tonus that removes thalamic T-channel inactivation (Llinas and Steriade, 2006).
    T-channel activity controls GABA synapses While the functional links between GABA IPSPs and LTS generation in the thalamic network have been studied for many years (Deschenes et al., 1984, Steriade et al., 1993), the reverse relationship has only recently started to be investigated (Pigeat et al., 2015, Sieber et al., 2013). Calcium imaging studies in NRT neurons showed that LTSs are associated with a widespread dendritic calcium influx via T-channels (Chausson et al., 2013, Crandall et al., 2010) and combining somatodendritic recordings, calcium imaging and computational modelling Connelly et al. (2015) further demonstrated that LTSs are global events that occur synchronously throughout the dendritic tree. In view of the existence of dendrodendritic synapses between NRT neurons, at least in certain species (Deschenes et al., 1985, Pinault et al., 1997, Yen et al., 1985), one may speculate that distal dendrite T-currents could contribute to dendritic GABA release and activation of these intra-NRT GABAergic synapses. In addition, a recent study demonstrated the existence of T-channel and syntaxin1A complexes in rat brains and showed a clear colocalization of these proteins in NRT neurons (Weiss et al., 2012), suggesting the potential involvement of T-channels in the synaptic mechanism of GABA release.