Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence

Abstract

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L185L to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders.

Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation

“…Whether, and how, PV+ interneuron-driven dynamics affect ‘structural’ plasticity in CA1 remains an open question. Recent studies suggest that these neurons themselves undergo synaptic remodelling as a function of memory formation3637. Intriguingly, disruption of sleep in the hours following learning has also been shown to impair structural plasticity in CA1 pyramidal neurons’ dendritic spines38.…”

RNA Editing—Systemic Relevance and Clue to Disease Mechanisms?

“…In the context of the rather low neuronal ambient glycine concentration in the hippocampus, presynaptic RNA-edited GlyRs were indeed shown to facilitate neurotransmitter release and contribute to gain-of-function of the affected neuron types, which elicited neuropsychiatric symptoms like cognitive dysfunction or persistence of contextual fear memory in our animal model. The different symptoms depended on the neuron type that expressed the RNA-edited GlyR variant, namely glutamatergic principle neurons (Camk2a-Cre) and parvalbumin-positive neurons (Pvalb-Cre), respectively (Winkelmann et al, 2014; Çalişkan et al, 2016; Figures 5C,D). As these symptoms of the genetically targeted mice are reminiscent of the disease symptomatology of TLE patients, we are currently investigating whether novel molecular and chemical tools (antagonists of RNA-edited GlyRs) are able to identify the neuron types with increased GlyR RNA editing in the hippocampus of patients with TLE and to counterbalance GlyR-dependent changes in neural network excitability.…”

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

“…C, expanded view of a GlyR ␣3L response to 1000 M glycine. IV relationships at the indicated time points (1)(2)(3)(4) are shown in D. D, IV relationships of homomeric GlyR ␣3L channels during current desensitization in response to 1000 M glycine. Note that the IV relationships at peak are linear and become inwardly rectifying upon desensitization.…”

“…GlyRs are involved in locomotion and the processing of visual, acoustic, and sensory signals. Aberrant function is associated with neuropathic pain and hyperekplexia (startle disease) as well as the pathophysiology of temporal lobe epilepsy and autism spectrum disorder (3)(4)(5)(6)(7). The family of GlyRs comprises five genes in humans: GLRA1-4, coding for the subunits GlyR ␣1-4, and GLRB, coding for GlyR ␤ (2,8).…”

“…Characteristic IV relationships were identified for many homo-and heteromeric ion channels, including members of the transient receptor potential (TRP) channel family (30,31). However, in the case of GlyRs, detailed information about isoform-specific characteristics of IV relationships is not available, especially for ␣2-and ␣3-containing GlyRs that are involved in neuropathic pain, temporal lobe epilepsy, and autism spectrum disorder (3)(4)(5)(6). Here, using the same (HEK293T) cellular expression system and the same experimental setup, we reveal essential information about characteristic IV relations of recombinant homomeric GlyR ␣2 and ␣3 channels.…”