Seite - (000186) - in Biomedical Chemistry: Current Trends and Developments

toxicity and eventually neuronal death (Zoghbi, 2000; Ross, 2004). In a number of SCAs, disruption of dendritic Ca2+ spikes through stimulation of AMPARs in Purkinje cells, and subsequent downstream signaling, is associated with disease pathology (Carlson, 2009). For instance, in SCA1, mutant ataxin 1 disrupts motor function by affecting synaptic plasticity in Purkinje cells, associated with an increase in intracellular calcium levels through glutamate receptors (Clark, 1997; Serra, 2004). In SCA5, mutations in β-III spectrin contribute to the stabilization of EAAT4 at the cell surface, affecting glutamatergic signaling (Ikeda, 2006). In SCA6, there is an accumulation of mutant Ca2+ channels which leads to an increase in intracellular calcium (Gatchel, 2005). Status epilepticus (SE) describes a persistent epileptic state during which epileptic seizures are unceasing and self-sustaining (Chen, 2007; Meldrum, 2007). Simultaneously with changes in inhibitory neurotransmission, AMPA and NMDARs subunits are recruited to the plasma membrane at synaptic sites, forming additional glutamate receptors, further increasing excitability (Wasterlain, 2009). For instance, GluN1 subunit translocates from extrasynaptic to synaptic sites, increasing the number of functional NMDARs at the synapse (Chen, 2007). Furthermore, changes in synaptic enzymes may also contribute to increased excitability, such as the autophosphorilation of Ca2+ calmodulin-dependent protein kinase II, which may increase glutamate release (Wasterlain, 1992). Seizures can also induce rapid changes in AMPARs subunit composition and function, particularly involving a decrease in GluA2 subunit, with subsequent increased Ca2+ permeability. This increases AMPARs mediated epileptogenesis in the hippocampus (Sanchez, 2001). In addicted persons, the uncontrollable urge to obtain drugs and relapse is associated with a pathological function of excitatory transmission (Winder, 2002). Glutamatergic interconnections occur between amygdala, NAc and PFC (Cardinal, 2002). The NAc core receives glutamatergic input from the PFC. This pathway is associated with learned behaviors in response to stimuli-predicting relevant motivational events and is highly relevant for drug-seeking (Sellings, 2003). Increased glutamate release occurs in the NAc following drug reinstatement (McFarland, 2003). This is mainly due to adaptations in