Learning from inhibition: Functional roles of hippocampal CA1 inhibition in spatial learning and memory

Abstract

Hippocampal inhibitory interneurons exert a powerful influence on learning and memory. Inhibitory interneurons are known to play a major role in many diseases that affect memory, and to strongly influence brain functions required for memory-related tasks. While previous studies involving genetic, optogenetic, and pharmacological manipulations have shown that hippocampal interneurons play essential roles in spatial and episodic learning and memory, exactly how interneurons affect local circuit computations during spatial navigation is not well understood. Given the significant anatomical, morphological, and functional heterogeneity in hippocampal interneurons, one may suspect cell-type specific roles in circuit computations. Here, we review emerging evidence of CA1 hippocampal interneurons' role in local circuit computations that support spatial learning and memory and discuss open questions about CA1 interneurons in spatial learning.

Figure 1.. Inhibitory roles in place field formation and maintenance

A. Simplified diagram of CA1 interneuron subclasses and their inhibitory synaptic targets on a pyramidal cell (Pyr.) with circles and triangle illustrating the location of the cell body of the interneuron and pyramidal cell, respectively. Calretinin (CR)- and vasoactive intestinal polypeptide (VIP)-expressing interneurons inhibit dendritic-targeting O-LM cells that primarily express somatostatin (SST), as well as soma-targeting parvalbumin-expressing basket cells (PVBC), thereby disinhibiting pyramidal cells. Basket cells co-expressing cholecystokinin (CCK) and VIP target the soma of pyramidal cells, whereas CCK and calbindin (CB)-expressing interneurons typically target the dendrites. Axo-axonic Chandelier (AAC) cells primarily target the axon initial segment. Note that the diagram focuses on interneurons described in this review and is not a comprehensive overview of hippocampal inhibitory circuitry. B. Prior work shows that spatially selective reduction in inhibition is not required for new field formation but may be important for stabilization and maintenance of new fields. Top, several types of inhibitory interneurons that synapsed onto a pyramidal cell were identified and targeted by their expression of vesicular GABA transporter (VGAT). The inhibitory neurons included multiple cell-types with multiple possible synaptic target locations. Bottom, no change in presynaptic inhibition was found prior to the lap where a new place field formed, but as the place field stabilized, the presynaptic interneuron developed “inverse” spatial selectivity such that it fired less than baseline levels at the postsynaptic pyramidal cell’s place field location [37]. C. Spatial selectivity in place cells is inducible with cell-type-specific reduction in inhibition. Optogenetic activation or silencing of axo-axonic cells targeting the axon initial segment of the pyramidal cell led to place field remapping in vivo during behavior [51]. Specifically, optogenetic silencing led to induction of new, persistent place fields at the photostimulated location. In contrast optogenetic activation led to no significance change in the number of place fields at the stimulation site although rare pre-existing place fields were suppressed.

Figure 2.. Inhibitory roles in learning goal-directed navigation

A. Place cells overrepresent behaviorally relevant locations such as reward zones and, while place fields tile the entire environment, more place fields cluster around these important locations. B. Vasoactive intestinal polypeptide (VIP)-expressing interneurons target other interneurons (Int.) that provides either perisomatic or dendritic inhibition onto pyramidal cells (Pyr.). In a recent study investigating a local CA1 disinhibitory circuit in goal-directed learning, optogenetically activating VIP interneurons (light blue) was found to induce faster learning of a new reward zone, as demonstrated by increased licking near the reward location [66]. Optogenetic silencing (yellow) led to impaired learning in the same goal-directed navigation task. These findings suggest that new goal learning (and its behavioral expression) is mediated by local inhibition and disinhibition of pyramidal cells. C. Left, consistent with these behavioral changes in B, optogenetic silencing of VIP neurons led to a reduced proportion of place cells with fields near the goal (yellow, inhibitory opsin ArchT in VIP interneurons). Right, in contrast to the observed behavioral effects, VIP optogenetic activation (light blue, excitatory opsin ChR2 in VIP interneurons) did not lead to observable changes in the proportion of goal-representing place cells. These results suggest that transient release of pyramidal cells from local inhibition is necessary, but not sufficient, to induce learning-dependent neuronal reorganization.