The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

Abstract

Brain states such as arousal and sleep play critical roles in memory encoding, storage, and recall. Recent studies have highlighted the role of engram neurons–populations of neurons activated during learning–in subsequent memory consolidation and recall. These engram populations are generally assumed to be glutamatergic, and the vast majority of data regarding the function of engram neurons have focused on glutamatergic pyramidal or granule cell populations in either the hippocampus, amygdala, or neocortex. Recent data suggest that sleep and wake states differentially regulate the activity and temporal dynamics of engram neurons. Two potential mechanisms for this regulation are either via direct regulation of glutamatergic engram neuron excitability and firing, or via state-dependent effects on interneuron populations–which in turn modulate the activity of glutamatergic engram neurons. Here, we will discuss recent findings related to the roles of interneurons in state-regulated memory processes and synaptic plasticity, and the potential therapeutic implications of understanding these mechanisms.

GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity

“…Importantly, besides pyramidal cells, PV interneurons innervate other types of inhibitory cells e.g. oriens lacunosum-moleculare (O-LM) and bistratified SST-positive interneurons but mainly other PV-positive INs 5 , 6 . It is important to note that specific subgroups of interneurons e.g.…”

“…VIP + INs target other interneurons (PV + and SST +) giving rise to neuronal disinhibition, one of the key phenomena involved in regulation of excitation/inhibition balance 7 . Recent studies, using genetically targeted recordings, enabled an insight into the mechanisms whereby distinct interneurons participate in the formation of hippocampal memory 5 , 6 . This expanding knowledge on GABAergic inhibition encouraged a more “holistic” approach considering additionally plasticity at GABAergic synapses and its interplay with the glutamatergic drive 8 – 11 .…”

“…Recent studies, using genetically targeted recordings, enabled an insight into the mechanisms whereby distinct interneurons participate in the formation of hippocampal memory 5,6 . This expanding knowledge on GABAergic inhibition encouraged a more "holistic" approach considering additionally plasticity at GABAergic synapses and its interplay with the glutamatergic drive [8][9][10][11] .…”

“…Considering the aforementioned importance of interneuron-interneuron inhibitory transmission and involvement of interneurons in memory formation, it seems appealing to explore the plasticity of GABAergic synaptic currents in the inhibitory neurons. To this end, we tested the impact of peptides affecting various types of integrins on GABAergic plasticity in parvalbumin-containing (PV + INs) and somatostatin-containing (SST + INs) interneurons, known to innervate distinct parts of pyramidal neurons (PV + INs-perisomatic, SST + INs-distal dendrites 4 ) and to differently shape the network activity and memory formation 5,6,[19][20][21] . We report that administration of distinct integrininterfering peptides induce cell-specific GABAergic plasticity.…”

Sleep-dependent engram reactivation during hippocampal memory consolidation is associated with subregion-specific biosynthetic changes

“…7c). 45 DEGs mapped to the synaptic membrane term. Transcripts downregulated in the superior blade after CFC included GABAA receptor subunit-encoding genes Gabra3, Gabrg3, and Gabra2, Rims3 (encoding a presynaptic regulator of exocytosis), Dcc (encoding a protein with pre and postsynaptic roles in excitatory synapse plasticity), Lrfn5 (encoding a cell surface regulator of synapse assembly), Ache (encoding acetylcholinesterase), L1cam (encoding an presynaptic cell surface adhesion regulator), Trappc4 (trafficking protein particle complex 4, which is involved in dendrite development and endosome regulation), Kcnc2 (encoding voltage-gated potassium channel Kv3.2), Tenm2 (teneurin transmembrane protein 2), Cntnap4 (contactin associated protein-like 4, a regulator of GABAA receptor localization and transmission), and Ank1 (which links synaptic membrane proteins to the spectrin cytoskeleton) (Fig.…”