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Published on: May 12, 2014
Tsc1 Loss in VIP-Lineage Cortical Interneurons Results in More VIP+ Interneurons and Enhanced Excitability
Jia Sheng Hu1, Ruchi Malik1,2,3,4, Vikaas S Sohal1,2,3,4
1Department of Psychiatry, University of California San Francisco, San Francisco, CA 94158, USA.
Abstract:
The mammalian target of rapamycin (mTOR) signaling pathway is a powerful regulator of cell proliferation, growth, synapse maintenance and cell fate. While intensely studied for its role in cancer, the role of mTOR signaling is just beginning to be uncovered in specific cell types that are implicated in neurodevelopmental disorders. Previously, loss of the Tsc1 gene, which results in hyperactive mTOR, was shown to affect the function and molecular properties of GABAergic cortical interneurons (CINs) derived from the medial ganglionic eminence. To assess if other important classes of CINs could be impacted by mTOR dysfunction, we deleted Tsc1 in a caudal ganglionic eminence-derived interneuron group, the vasoactive intestinal peptide (VIP)+ subtype, whose activity disinhibits local circuits. Tsc1 mutant VIP+ CINs reduced their pattern of apoptosis from postnatal days 15-20, resulting in increased VIP+ CINs. The mutant CINs exhibited synaptic and electrophysiological properties that could contribute to the high rate of seizure activity in humans that harbor Tsc1 mutations.
Insights
Loss of the Tsc1 gene causes mTOR hyperactivity, increasing vasoactive intestinal peptide (VIP+) interneurons. These altered neurons may contribute to seizures seen in Tsc1 mutation patients.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- The mammalian target of rapamycin (mTOR) pathway regulates crucial cellular processes like proliferation and fate.
- mTOR's role in neurodevelopmental disorders is under active investigation.
- Previous studies linked Tsc1 loss and mTOR hyperactivity to altered medial ganglionic eminence-derived cortical interneurons (CINs).
Purpose of the Study:
- To investigate the impact of mTOR dysfunction on caudal ganglionic eminence-derived VIP+ interneurons.
- To determine if Tsc1 mutations affect VIP+ CINs and contribute to associated neurological conditions.
Main Methods:
- Genetic deletion of the Tsc1 gene in VIP+ CINs.
- Analysis of apoptosis patterns during postnatal development (days 15-20).
- Assessment of synaptic and electrophysiological properties of mutant CINs.
Main Results:
- Tsc1 mutant VIP+ CINs showed reduced apoptosis, leading to an increased number of these interneurons.
- Mutant CINs displayed altered synaptic and electrophysiological characteristics.
- These cellular changes correlate with seizure activity observed in Tsc1 mutation patients.
Conclusions:
- mTOR hyperactivity due to Tsc1 loss impacts VIP+ interneuron development and function.
- Dysfunctional VIP+ CINs are a potential mechanism underlying seizures in Tsc1-related disorders.
- This study highlights the specific vulnerability of distinct interneuron populations to mTOR pathway dysregulation.
