Regulation of Hippocampal Memory by mTORC1 in Somatostatin Interneurons

Abstract

Translational control of long-term synaptic plasticity via Mechanistic Target Of Rapamycin Complex 1 (mTORC1) is crucial for hippocampal learning and memory. The role of mTORC1 is well characterized in excitatory principal cells but remains largely unaddressed in inhibitory interneurons. Here, we used cell-type-specific conditional knockout strategies to alter mTORC1 function selectively in somatostatin (SOM) inhibitory interneurons (SOM-INs). We found that, in male mice, upregulation and downregulation of SOM-IN mTORC1 activity bidirectionally regulates contextual fear and spatial memory consolidation. Moreover, contextual fear learning induced a metabotropic glutamate receptor type 1 (mGluR1)-mediated late long-term potentiation (LTP) of excitatory input synapses onto hippocampal SOM-INs that was dependent on mTORC1. Finally, the induction protocol for mTORC1-mediated late-LTP in SOM-INs regulated Schaffer collateral pathway LTP in pyramidal neurons. Therefore, mTORC1 activity in somatostatin interneurons contributes to learning-induced persistent plasticity of their excitatory synaptic inputs and hippocampal memory consolidation, uncovering a role of mTORC1 in inhibitory circuits for memory.

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

“…For current-clamp recordings, the intracellular recording solution contained (in mM) 120 KMeSO 3 , 0.5 EGTA, 10 KCl, 10 HEPES, 4 Mg-ATP, 0.3 GTP-tris, and 10 Di-Na phosphocreatine. Membrane properties were recorded as previously [21] in current clamp at a membrane potential (Vm) of − 60 mV in ACSF containing the NMDA receptor blocker DL-2-amino-5-phosphonovaleric acid (AP5 50 μM; Tocris Biosciences), the non-NMDA receptor blocker 6,7-dinitroquinoxaline-2,3-dione (DNQX 25 μM; Tocris Biosciences), and the GABA A receptor blocker GABAzine (10 μM; Abcam, Canada).…”

TRPC1 mediates slow excitatory synaptic transmission in hippocampal oriens/alveus interneurons

“…Given our evidence of the role of TRPC1 in excitatory synaptic transmission in inhibitory interneurons, it is interesting to speculate that some of these synaptic and behavioural effects may involve TRPCs in inhibitory neurons, possibly O/A interneurons. Hebbian mGluR1a-mediated LTP at excitatory synapses onto O/A INs, and more specifically onto interneurons that express somatostatin (SOM INs), was shown to upregulate persistently LTP magnitude at Schaffer collateral-CA1 pyramidal cell synapses via a disinhibition mechanism [5,11,75,76]. Moreover, impairing mGluR1a-mediated LTP by interfering with mTORC1 function specifically in somatostatin interneurons impairs hippocampal spatial and contextual fear memory consolidation [11,77,78].…”

“…Hebbian mGluR1a-mediated LTP at excitatory synapses onto O/A INs, and more specifically onto interneurons that express somatostatin (SOM INs), was shown to upregulate persistently LTP magnitude at Schaffer collateral-CA1 pyramidal cell synapses via a disinhibition mechanism [5,11,75,76]. Moreover, impairing mGluR1a-mediated LTP by interfering with mTORC1 function specifically in somatostatin interneurons impairs hippocampal spatial and contextual fear memory consolidation [11,77,78]. Thus since mGluR1a-mediated slow excitatory transmission in O/A INs is dependent on TRPC1 and that TRP channels blockade prevents LTP induction in O/A INs [13], TRPC1 function in interneurons may be important for hippocampal-dependent learning and memory.…”

“…This LTP depends on the activation of metabotropic glutamate receptor subtype 1a (mGluR1a) and postsynaptic calcium elevation [9,10]. At the circuit level, LTP of O/A IN input synapses regulates metaplasticity of CA1 pyramidal cells [5] and hippocampal long-term memory consolidation [11] .…”

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

“…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 . While numerous studies have focussed on the effects of Tsc1/2 deletion, and mTOR dysregulation, on cortical and hippocampal excitatory cells (Tavazoie et al, 2005, Bateup et al, 2011, Bateup et al, 2013, Nie et al, 2015, only few studies have addressed whether and how Tsc1/2 deletion affects cortical GABAergic circuit development (Zhao and Yoshii, 2019, Malik et al, 2019, Artinian et al, 2019. In particular, whether it plays different roles in specific GABAergic populations is not known.…”