Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice

Abstract

Background: Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability. TSC1 and TSC2 are repressors of the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. However, synaptic inhibition arises from multiple types of inhibitory interneurons and how changes in specific interneurons contribute to TSC remains largely unknown. In the present work, we determined the effect of conditional Tsc1 haploinsufficiency in a specific subgroup of inhibitory cells on hippocampal function in mice. Methods: We investigated the consequences of conditional heterozygous knockout of Tsc1 in MGE-derived inhibitory cells by crossing Nkx2.1 Cre/wt ;Tsc1 f/f mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks. Results: We detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cellspecific-upregulated mTORC1 signaling. At the behavioral level, Nkx2.1 Cre/wt ;Tsc1 f/wt mice exhibited intact contextual fear memory, but impaired contextual fear discrimination. They displayed intact spatial learning and reference memory but impairment in spatial working memory. Whole-cell recordings in hippocampal slices of Nkx2.1 Cre/wt ;Tsc1 f/wt mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and

Sensitive period for rescuing parvalbumin interneurons connectivity and social behavior deficits caused by TSC1 loss

“…5f ). These results are consistent with a recent study showing that pyramidal cell synaptic inhibition is reduced in the hippocampus of adult Nkx2.1-Cre;Tsc1 flox/+ mice 15 . Overall, these results confirm that embryonic deletion of Tsc1 has opposite effects on PV perisomatic synapse formation and maintenance, initially accelerating the formation of PV synaptic innervation and subsequently impairing perisomatic synapses at the maturation phase.…”

“…Over the past 15 years, numerous studies have provided evidence that alterations in E/I balance may be involved in many mouse models of monogenetic autism, however the nature of the underlying mechanisms are heterogeneous thus highlighting that it is critical to understand what sort of circuit alterations are caused by specific genetic mutations 6 . While numerous studies have focussed on the effects of Tsc1/2 deletion, and mTOR dysregulation, on cortical and hippocampal excitatory cells 7 – 10 , only few studies have addressed whether and how Tsc1/2 deletion affects cortical GABAergic circuit development 11 – 15 . In particular, whether it plays different roles in specific GABAergic populations is not known.…”

Effects of Mutations in TSC Genes on Neurodevelopment and Synaptic Transmission

“…Interestingly, those seizure resemble what is observed in human [ 38 ]. While all three models present with varying degrees of behavioral and cognitive deficits [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], their relationship with the rich variety of manifestations observed in ASD and TANDs symptoms in humans is not necessarily straightforward.…”

Neuron–Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures

“…This was a surprising finding, as TSC and epilepsy are generally associated with increased neuronal activity. Indeed TSC neurons are hyperactive in culture [ 14 ] and mouse studies have shown decreased synaptic inhibition [ 17 ] and reductions in GABA receptor GABA A R causing hyperexcitability [ 16 ]. It is important to note that VGAT is expressed on GABAergic vesicles located at the presynapse.…”

“…Previous studies have shown hyperactive neuronal networks in TSC mouse models and stem cell-derived human neuron cultures [ 9 , 14 , 15 , 16 ]. These changes in network excitability are often associated with changes in synaptic balance, like a decrease in synaptic inhibition [ 17 ] or a decrease in γ-aminobutyric acid (GABA) receptors [ 9 , 16 ]. It is well known that astrocytes play crucial roles in neurodevelopment and can directly influence synaptic transmission [ 18 ].…”