Abstract
BackgroundMutations 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.MethodsWe investigated the consequences of conditional heterozygous knockout of Tsc1 in MGE-derived inhibitory cells by crossing Nkx2.1Cre/wt;Tsc1f/f mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks.ResultsWe detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cell-specific-upregulated mTORC1 signaling. At the behavioral level, Nkx2.1Cre/wt;Tsc1f/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 Nkx2.1Cre/wt;Tsc1f/wt mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and Nkx2.1-expressing inhibitory cells. Using optogenetic activation of Nkx2.1 interneurons in slices of Nkx2.1Cre/wt;Tsc1f/wt mice, we found a decrease in synaptic inhibition of pyramidal cells. Chronic, but not acute treatment, with the mTORC1 inhibitor rapamycin reversed the impairment in synaptic inhibition.ConclusionsOur results indicate that Tsc1 haploinsufficiency in MGE-derived inhibitory cells upregulates mTORC1 activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory. Thus, selective dysregulation of mTORC1 function in Nkx2.1-expressing inhibitory cells appears sufficient to impair synaptic inhibition and contributes to cognitive deficits in the Tsc1 mouse model of TSC.
Highlights
Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability
Using optogenetic activation of Nkx2.1 interneurons in slices of Nkx2.1Cre/wt;Tsc1f/wt mice, we found a decrease in synaptic inhibition of pyramidal cells
Our results indicate that Tsc1 haploinsufficiency in medial ganglionic eminence (MGE)-derived inhibitory cells upregulates mechanistic target of rapamycin complex 1 (mTORC1) activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory
Summary
Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. Mice with heterozygous mutations in Tsc have deficits in hippocampus-dependent contextual fear and spatial learning, in the absence of cerebral pathology [8]. Mice with heterozygous mutations in Tsc have impairments in hippocampus-dependent spatial reference and working memory [9], as well as contextual fear discrimination [9, 10]. These learning and memory deficits are associated with impairments in hippocampal synaptic plasticity. MGluR LTD is impaired after postnatal deletion of Tsc in mouse CA1 hippocampus in vivo [12] and in mice with conditional heterozygous Tsc knockout in forebrain excitatory neurons [13]
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