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31-33. In particular, significant up-regulation of IL-1R/TLR pathway-related microRNAs such as miR21, miR146a and miR155 has been reported during epileptogenesis in experimental temporal lobe epilepsy 34, as well in focal cortical dysplasia (FCD) tissue samples 94 and in glioneuronal tumors 35.
Morphological and functional astrocytic abnormalities, with a prominent population of reactive astrocytes, represent a major feature of TSC brain pathology. Furthermore,evidence is emerging supporting the potential of astrogliosis to play a pri- mary or contributing role to neurologic dysfunction in TSC (for reviews, see 29, 95). In particular, few recent studies described in details the morphological and immunopheno- typical features of astrogliosis in TSC, providing evidence of mTOR activation in reactive astrocytes within the tuber, as well as in epileptogenic perituberal cortex 96-98. These observations suggest that up-regulation of the mTOR pathway could contribute to neu- rologic dysfunction in TSC by directly affecting not only neurons but also astrocytes 29, 95, 99. Accordingly, astroglial abnormalities have been reported in several mouse TSC models, including the TSC1 conditional knockout mice, in which glia abnormalities are partial rescued by the mTOR inhibitor rapamycin 100.
Since experimentally induced seizures in rodents trigger astrogliosis and pro- duction of cytokines, such as IL-1β 29, 30 it is still an open issue whether the dysregulation of astrocyte immune-inflammatory responses, involving also the induction of inflamma- tion-related microRNAs, could simply represent the consequence of recurrent seizures. However, the observation of prenatal activation of the IL-1R/TLR signaling in TSC brain 17, 18 suggests that the induction of these signaling pathways could be intrinsic to the developmental lesion and linked to the deregulation of the mTOR pathway. In line with this, a recent study shows over-activation of IL-1β signaling pathway in astrocytes before epilepsy onset in a mouse model of TSC 19.
In contrast, it is likely that pro-inflammatory cytokines, such as IL-1β, may further acti- vate astrocytes within tubers, inducing NF-κB-sensitive microRNAs, as supported by our in vitro data. It is likely that expression of miR146a in astrocytes may represent an attempt to regulate the inflammatory response triggered by IL-1β and counteract other co-induced pro-inflammatory miRNAs, as suggested by our observations. This might be particularly interesting, considering that activation of astrocyte-mediated inflammatory response may alter neural network excitability 29, 30, 101, 102. Whether induction of NF-κB- sensitive microRNAs may also influence astrocyte proliferation and/or modulate the mTOR pathway deserves further investigation.
The use of fixed material, representing the chronic stage of the human disease, cannot give information on the timecourse of the inflammation-related microRNAs during epileptogenesis in TSC. Thus mouse TSC models may be useful to provide this information and to further study the consequences of their modulation in vivo on TSC astroglial abnormalities and epileptogenesis. Recent evidence about developmental reg- ulation of miRNAs, including NF-κB-sensitive microRNAs, in human astrocytes 103, open the question whether dysregulation inflammation-related microRNAs in fetal brain may also contribute to neurobehavioral abnormalities in TSC 89, 90.