Inhibiting Inhibition: Circuit-level and Behavioral Functions of Interneuron-Specific Interneurons in Cortico-Hippocampal Networks
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The dentate gyrus (DG) acts as a gateway to the hippocampus processing multimodal sensory information arriving from neocortex via the entorhinal cortex. DG principal neurons, the granule cells (GCs), translate the rich cortical input into a sparse code for downstream hippocampal areas under inhibitory control by a small yet diverse set of GABAergic interneurons (INs). INs themselves receive GABAergic inhibition and one major source of inhibition is mediated by specialized, vasoactive intestinal peptide(VIP)-expressing INs, which preferentially innervate other INs. VIP+ INs, thus, provide disinhibitory control to the network, however, our knowledge about these INs in DG networks was scarce. Several questions with respect to IN-specific inhibition in the DG remained to be answered: (1) What are the functional and anatomical properties of VIP INs? (2) What is the molecular specification of VIP INs? (3) What are the precise cellular and subcellular targets of VIP INs? (4) What is the functional consequence of VIP IN-mediated disinhibition on hippocampal circuits? (5) Lastly, what is the behavioral relevance of VIP IN-mediated disinhibition? To answer these questions, in a collaborative effort with our Taiwanese partner, we applied a combined neuroanatomical, electrophysiological and optogenetic approach. To selectively target and manipulate VIP+ INs, we utilized a VIP-Cre transgenic mouse line to drive the expression of either genetically encoded reporters (tdTomato in Ai14 and Ai9 transgenic lines) or virally transfected constructs (Channelrhodopsin2-YFP). Whole-cell recordings in acute slice from Cre- VIP::Ai14 mice revealed that VIP+ INs have heterogeneous physiological properties. clearly distinct from those of GCs. Hierarchical cluster analysis identified 3 major electrophysiological subtypes, characterized by their discharge patterns – (1) fast-adapting, (2) regular-spiking and (3) irregular-spiking. Subsequent visualization of the recorded and intracellularly-filled INs showed that the morphology of VIP+ INs is also heterogeneous and these INs can be classified into 4 major subtypes: 1) Hilus-Projecting (HP) INs, (2) Molecular layer-projecting (MP) INs, (3) Bistratified INs, and (4) Trilaminar INs. Physiological and morphological subtypes showed low level of convergence, indicating a potential further level of functional diversification. Paired whole-cell recordings from VIP+ INs and neighboring neurons indicated a sparse local connectivity. Identified connections were inhibitory coupling with VIP+ and VIP- INs. Channelrhodopsin-mediated photostimulation of VIP+ INs evoked IPSCs with high probability in various types of DG INs, but low probability in GCs, further reflecting their preferential innervation of IN and their role as disinhibitory elements in DG microcircuits. Stimulation of the perforant path input from the entorhinal cortex produced both direct excitation and feedforwad inhibition in VIP+ INs. The synaptic dynamics during theta frequency stimulation shifted the balance from a predominant inhibition to excitation, resulting in a delayed recruitment of the INs. Finally, pharmacological experiments using a GABAB receptor agonist further demonstrated, that in addition to the GABAA-mediated fast, synaptic inhibition, DG IN types receive slow GABAB receptor-mediated inhibition, modulating their excitability in a type-specific manner. In summary, the data obtained in this project provides a systematic electrophysiological, morphological and microcircuit characterization of VIP+ INs in the rodent DG. The results demonstrate that VIP+ INs primarily innervate other DG IN types and provide disinhibition to the DG network. Their physiological and synaptic properties further indicate that they are recruited to network activity with latency. The existence of 3 physiological and 4 morphological subtypes reflect a functional differentiation of VIP+ IN in these circuits. The expression of reporter molecules in a subset of GCs precluded an optogenetic and chemogenetic analysis of the behavioral analysis of VIP+ IN function in DG circuits. Further experiments in which the expression of the reporters to GABAergic INs by an additional regulatory element (e.g. Dlx-5/6) will be required.
Publications
-
Morpho‐physiological properties and connectivity of vasoactive intestinal polypeptide‐expressing interneurons in the mouse hippocampal dentate gyrus. Journal of Comparative Neurology.
Wei, Yu‐Ting; Wu, Jei‐Wei; Yeh, Chia‐Wei; Shen, Hung‐Chang; Wu, Kun‐Pin; Vida, Imre & Lien, Cheng‐Chang
-
GABAB Receptor-mediated effects in VIP-Expressing Interneurons of the Dentate Gyrus. 116th Annual Meeting of the Anatomische Gesellschaft, Joint Meeting with Anatomical Society UK, 2022 Berlin. Poster presentation
He Z., Ishihara Y., Lien C.-C. & Vida I.
-
GABAB Receptor-mediated effects in VIP-Expressing Interneurons of the Dentate Gyrus. FENS Forum, Glasgow, UK. Poster presentation. (2022)
He Z., Ishihara Y., Lien C.-C. & Vida I.
