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  • br Functional consequences of ADK regulation on neuronal exc

    2023-12-08


    Functional consequences of ADK regulation on neuronal excitability Adenosine modulates neuronal excitability via activation of the high affinity A1 or A2A, low-affinity A2B, or low abundance A3 adenosine receptors that feed into a multitude of different neuronal and astrocytic pathways (Blum et al., 2003, Sebastiao and Ribeiro, 2009a, Sebastiao and Ribeiro, 2009b, Boison et al., 2010). In the context of epilepsy, the predominant research focus has been on adenosine signaling via inhibitory A1 and facilitory A2A receptors (Fig. 1). In comparison to the A2AR where expression is primarily localized to the striatum (Rosin et al., 1998, Ferre et al., 2007), the A1R is widespread throughout the limbic system with greatest expression levels in the hippocampus and cortex [(Reppert et al., 1991); Allen Brain Atlas, www.brain-map.org]. However, seizure activity has been shown to alter the expression levels of both the A1R and A2AR. Rats that were either stimulated by intraamygdalar kindling or received an intraperitoneal injection of KA had a robust increase in cortical A2A expression and activity, while the A1R was downregulated (Rebola et al., 2005). Likewise in the hippocampus there is a decrease in A1R following chemical (Cremer et al., 2009) or electrical kindling (Aden et al., 2004). Depending on the subcellular localization, the A1R has the capabilities to modulate both the pre- and postsynaptic activity of neurons (Fig. 1). Numerous lines of research have established that adenosine activation of the A1R inhibits excitatory post-synaptic potentials [for review see (Dunwiddie and Masino, 2001)]. More specifically, in the mossy fiber synapse, A1R activation inhibits P/Q- and N-type voltage gated Ca2+ epigenetics methods that subsequently attenuate synaptic transmission by reducing the release probability of excitatory neurotransmitters (Gundlfinger et al., 2007). On the post-synaptic membrane of excitatory neurons, A1R modulates the activity of inwardly rectifying K+ channels, which can directly stabilize the membrane potential or hyperpolarize the cell (Luscher et al., 1997, Takigawa and Alzheimer, 2002). Recently, the A1R has also been found to reduce GABAA-receptor dependent depolarizations that occur during a seizure (Ilie et al., 2012). Thus, A1R modulation of network excitability has the capability to exert a profound anticonvulsant effect. The pathological state of network hyperexcitability leading to seizures in epilepsy is in part due to an ADK-mediated reduction in adenosine tone leading to diminished A1R activity (Fig. 1). Injection of KA in either the hippocampus (Gouder et al., 2004) or amygdala (Li et al., 2007a, Li et al., 2008b, Li et al., 2012) causes a focal injury that is confined to the ipsilateral hemisphere and is characterized by overt astrogliosis and increased ADK expression (Fig. 2). These epileptic hallmarks are accompanied by increased network excitability and electrographic seizures (Gouder et al., 2004, Li et al., 2007a, Li et al., 2008b, Li et al., 2012). Importantly, seizure activity in KA injected mice is attenuated by either 5-iodotubercidin, an ADK inhibitor (Gouder et al., 2004) or adenosine that is focally delivered by transplanted ADK-deficient embryonic stem cells (Li et al., 2008b). Further evidence that dysregulation of the adenosine system aggravates an epileptic phenotype comes from a series of studies that employ A1R-knockout mice or antagonists. First, independent of a focal injury, A1R knockout mice have spontaneous electrographic seizures that occur in the CA3 subregion of the hippocampus despite normal wild type levels of ADK expression (Li et al., 2007a). Second, using a low dose of KA (1nmol) injected into the hippocampus of A1R knockout mice, seizure severity is escalated from non-convulsive (observed in wild type mice injected with the same dose) to convulsive during SE. Moreover, the A1R knockout mice die within 5days of KA injection and there is extensive neuronal cell death within both the ipsi- and contralateral hippocampus. Pathology in the wild type mice is confined to the ipsilateral injection site (Fedele et al., 2006). However, administration of a non-convulsive dose of an A1R antagonist to intraamygdaloid injected KA mice causes a synchronization of epileptic foci and subsequent generalization of seizures to the cortex (Li et al., 2012). To distinguish between ADK and A1R dependent effects on neuronal excitability in temporal lobe epilepsy, Li et al. compared the seizure phenotype of epileptic wild type mice 4weeks after the intraamygdaloid KA injection, and the spontaneous seizures in the Adk-tg mice that overexpress ADK in brain and have normal A1R expression and in the A1R knockout mice which have normal ADK expression. Remarkably, all three models displayed a similar seizure phenotype indicating that either overexpression of ADK alone or loss of the A1R alone is sufficient to trigger spontaneous electrographic seizures (Li et al., 2007a, Li et al., 2008a). Together, these data implicate that disruption of adenosine signaling can affect neuronal excitability at different levels. However, considering that ADK acts upstream of the A1R; overexpression of ADK is expected to exert dominant effects over A1R expression changes.