The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability

Abstract

The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.

Encoding of contextual fear memory in hippocampal–amygdala circuit

“…Thus, it is noteworthy that only a fraction of vCA1 and BA neurons labeled selectivity than the dCA1 28,35 . Previous studies have implicated the vCA1 in contextual fear learning 3,6,[36][37][38] . We found that silencing vCA1-BA activity during fear conditioning decreased conditioned fear responses 24 h later, indicating that vCA1-BA activity is involved in the acquisition of contextual fear memory, consistent with a previous report 14 .…”

The Synaptic and Neuronal Functions of the X‐Linked Intellectual Disability Protein Interleukin‐1 Receptor Accessory Protein Like 1 (IL1RAPL1)

“…Functionally, the reduction of excitatory synapse number results in a little, not significant reduction of mEPSC and in LTP impairment only with a paradigm of theta burst stimulation (LTP for high‐frequency stimulation is comparable to WT mice). Data of behavioral studies show that IL1RAPL1 knockout male mice show deficits in spatial recognition, and fear memories (Pavlowsky et al , ; Houbaert et al , ; Yasumura et al , ; Zhang et al , ; Montani et al , ). Social interaction and motor coordination are improved in IL1RAPL1 knockout mice, but the motor learning ability is comparable with wild‐type mice (Yasumura et al , ).…”

“…Present studies with mutant mice revealed that the ablation of IL1RAPL1 affects diverse brain functions including learning, memory, behavioral flexibility, locomotor activity, and anxiety (Pavlowsky et al , ; Yasumura et al , ; Zhang et al , ; Montani et al , ). In particular, hippocampal‐dependent memory is strongly impaired.…”

“…The decrease in spine density in IL1RAPL1 mutant mice will cause excitation and inhibition imbalances in many brain circuits since IL1RAPL1 is widely expressed in the brain (Carrie et al , ; Houbaert et al , ; Zhang et al , ). Thus, it is reasonable that multiple brain functions are affected by the mutation (Yasumura et al , ).…”

“…For instance, the altered I/E balance at the hippocampus‐BLA (Basolateral amygdala) projections leads to a deficit in contextual memory expression rather than memory formation, thereby suggesting that cognitive disability in humans may result from the deficiency of synapses involved at different steps of the cognitive process, including memory restitution and behavioral expression (Zhang et al , ).…”