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  • Although the role of mossy fiber sprouting in

    2024-11-29

    Although the role of mossy fiber sprouting in epileptogenesis has been challenged (Elmer et al., 1997, Nissinen et al., 2001), in addition to astrogliosis, mossy fiber sprouting is one of the characteristic histopathological findings in TLE (Kharatishvili et al., 2006, Pitkanen et al., 2007, Represa et al., 1993, Sloviter et al., 2006, Sutula et al., 1988). The loss of normal postsynaptic targets of granule neurons may be the cause for mossy fiber sprouting, a hypothesis supported by findings that the degree of mossy fiber sprouting is correlated to the degree of neuronal cell loss (Cavazos and Cross, 2006). However, seizure-induced plasticity shows a different pattern of reorganization in the immature SR 57227 hydrochloride mg (Cross and Cavazos, 2007). In adult brain, sprouting mossy fibers grow aberrant collaterals into the inner molecular layer of the dentate gyrus, where they preferentially make synaptic contacts with dendrites of other granule neurons, leading to the formation of excitatory feedback circuits (Buckmaster et al., 2002, Scharfman et al., 2003).
    Neuromodulation by adenosine Adenosine is an ubiquitous modulator of synaptic transmission and neuronal activity, exerting most of its functions via activation of the high-affinity inhibitory adenosine A1 and excitatory A2A receptors, while the low-affinity or low-abundance A2B and A3 receptors provide an additional layer of modulatory receptor crosstalk (Dunwiddie and Masino, 2001, Fredholm et al., 2005a, Fredholm et al., 2005b, Fredholm et al., 2001). Different affinities of these receptors for adenosine and highly specific spatial distribution patterns within the brain allow a high degree of complexity in the effects of adenosine and modulation of the action of other neurotransmitters or modulators (Cunha-Reis et al., 2007, Sebastiao and Ribeiro, 2000). Thus, adenosine controls many brain functions in physiological and pathophysiological conditions (Fredholm et al., 2005a, Fredholm et al., 2005b) and has potent anticonvulsant (Boison, 2005, Dragunow, 1986, Dunwiddie, 1999) and neuroprotective (Cunha, 2005, Dragunow and Faull, 1988, Ribeiro, 2005) properties. Due to these properties of adenosine, an adenosine-based pharmacopoeia has been established for a variety of conditions (Jacobson and Gao, 2006) including the development of adenosine-based cell therapies for the treatment of focal epilepsies (Boison, 2007a, Boison, 2007b).
    Regulation of endogenous adenosine Due to the widespread distribution of adenosine receptors a tight regulation of endogenous levels of adenosine becomes a necessity. Extracellular and synaptic levels of adenosine are a function of adenosine formation, clearance and metabolism. As detailed below, recent evidence suggests that astrocytes play a key role in regulating the levels of endogenous extracellular adenosine (Boison, 2006, Haydon and Carmignoto, 2006), possibly by an adenosine cycle involving the vesicular release of ATP, extracellular degradation of ATP to adenosine, uptake of adenosine via nucleoside transporters and intracellular phosphorylation of adenosine to AMP.
    Insights from mouse models of epileptogenesis The expression of ADK is characterized by striking plasticity. Remarkably, enzyme expression undergoes a coordinated switch from neuronal to astrocytic expression during the early postnatal development of the mouse brain (Studer et al., 2006); thus high neuronal ADK expression in the developing brain may explain the heightened seizure susceptibility of infants (Studer et al., 2006). Most importantly, ADK expression undergoes acute and chronic changes in response to various stress factors.
    Seizure susceptibility in adenosine kinase transgenic mice To answer the question whether astrogliosis or upregulation of ADK is the primary cause for epileptogenesis, transgenic mice were created with altered levels of ambient adenosine due to either reduction or overexpression of ADK. Global genetic disruption of ADK led to hepatic steatosis and perinatal lethality (Boison et al., 2002b) precluding any further studies of epileptogenesis. However, mutant mice overexpressing transgenic ADK in an ADK-deficient background (Adk-tg) have been generated recently (Fedele et al., 2005). Due to the lack of endogenous ADK, adenosine levels in these mice are exclusively under the control of a loxP flanked transgenic ADK, which is overexpressed in brain and exhibits a novel expression of ADK in neurons, particularly in the hippocampal CA3 region (Fedele et al., 2005). A reduced tone of ambient adenosine was demonstrated in brain slices derived from Adk-tg mice. Thus, increased pictrotoxin-induced seizure activity, as well as the lack of changes in the EPSP response after pharmacological blockade of the A1R in mossy fiber CA3 synapses, was consistent with a reduction in hippocampal adenosine levels. Concordantly, A1R dependent adenosine-mediated inhibition of the EPSP amplitude could be restored by inhibition of ADK (Fedele et al., 2005). As a result of the mutation and reduced levels of protective adenosine, the animals exhibit aggravated cell death in ischemia (Pignataro et al., 2007b). Most notably, transgenic overexpression of ADK in CA3 was associated with spontaneous electrographic CA3 seizures – and this in the absence of astrogliosis – at a frequency of 4.8±1.5 seizures per hour with each seizure lasting 26.7±13.2s. Remarkably, CA3 seizures in Adk-tg mice were highly similar to CA3 seizures in KA treated epileptic mice (4.3±1.5 seizures per hour, each lasting 17.5±5.8s (Li et al., 2008). It is important to note that in mutant animals only modest increases in forebrain ADK (147% of normal) were sufficient to elicit spontaneous seizures (Li et al., 2008). This correlates well with the 1.8-fold increase of ADK activity in hippocampi of kainic acid treated epileptic mice (Gouder et al., 2004). SR 57227 hydrochloride mg These findings imply that tight regulation of adenosine levels by ADK is a necessity and that moderate overexpression of ADK is sufficient to induce seizures.