Thalamus, timing and TSC1 deletions

Tuberous Sclerosis. Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by lack of function of the TSC1 or TSC2 tumor suppressor gene. With respect to the Central Nervous System, this disease is characterized by so-called tubers, benign tumors consisting of dysplastic neurons that are highly epileptogenic. Accordingly, TSC is one of the most common causes of West Syndrome. However, there is also evidence for neurological dysfunction beyond tubers. Increasing evidence suggests that the mutations alone can result in abnormalities of neuronal networks, resulting in epilepsy, intellectual disability or autism. The thalamus appears to be a key structure that is affected by this dysfunction. Now, a recent study in Cell explores the effects of TSC1 deletions at different developmental stages with respect to neuronal development in the thalamus.

Tuberous Sclerosis Complex. We have discussed TSC several times on this blog already, as the underlying molecular mechanism seems to be impaired in a much wider range of epilepsies and developmental disorders of the brain. In brief, TSC1 and TSC2 are tumor suppressor genes that inhibit the so-called mTOR pathway. This pathway is one of the master regulators of neuronal growth, and other recently discovered epilepsies caused by mutations in DEPDC5 or STRADA also seem to have alterations of the mTOR pathway. Likewise, many of the somatic mutations in hemimegalencephaly occur in genes in the mTOR pathway. The characteristic feature of TSC is tubers, benign tumor of the CNS that are highly epileptogenic. However, in TSC there also seems to be an impact of TSC1/TSC2 mutation independent of tubers. In order to assess the impact of TSC1 deletions in a particular brain region, Normand and collaborators generated mice with specific deletions in thalamic TSC1 expression. These deletions were inducible, i.e. the gene could be turned off at any given time during embryonal development.

Main findings in the study of Normand and collaborators. Early, but not late embryonic deletion of TSC1 leads to abnormal neuronal morphology and altered electrophysiological properties.

Main findings in the study of Normand and collaborators. Early, but not late embryonic deletion of TSC1 leads to abnormal neuronal morphology and altered electrophysiological properties.

The impact of early TSC1 deletions. When TSC1 was deleted at embryonal day 12, Normand and collaborators observed several effects in the thalamus. Basically, the neurons were enlarged, had increased projections to the cerebral cortex and the electrophysiology was altered with a higher amplitude of action potentials. Also, this particular change in the thalamus resulted in profound changes in network properties. Even though nothing had happened to the TSC1 gene expression in cortex, there was increased neuronal network activity, a secondary effect of thalamic TSC1 deletion. Interestingly, when the authors turned off the gene a few days later, many of these changes were not seen anymore. This suggests that the timing of TSC1 deletions is crucial and that early neuronal development is particularly sensitive to TSC1 dysfunction.

Relevance for EuroEPINOMICS. The study by Normand and collaborators reminds us that neuronal development is a critical point to take into account when we are trying to understand why a certain mutation results in epilepsy. In genetic seizure disorders, our paradigm to explain the molecular mechanism is the channelopathy hypothesis: mutations result in dysfunction of ion channels on the neuronal membrane, therefore individual neurons are hyperexcitable, which then results in hyperexcitability of neuronal networks and eventually in the tendency to have seizures. This hypothesis, however, does not take into account that mutations might also have a developmental impact on the Central Nervous System, which not only affects membrane excitability, but also neuronal architecture or synaptic connections. Basically, there might be other aspects to ion channel disorders that are related to neuronal growth and development.

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