Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

Abstract

Fear learning and memory are crucial for animal survival. Abnormal fear memory is a hallmark of many neuropsychiatric disorders. Appropriate neuronal activation and excitability in the basolateral amygdala (BLA) are necessary for the formation of fear memory. The gene cylindromatosis (Cyld), which encodes a lysine-63 deubiquitinase, is expressed in several brain regions including the amygdala. The functions of the cylindromatosis protein (CYLD) in the regulation of the neuronal activity, neural circuits and fear memory, remain largely unknown, however. Here, we report that Cyld knockout impairs amygdala-dependent tone-cued fear memory. The number of c-Fos+ neurons responding to the tone-cued fear test was reduced in the BLA of Cyld–/– mice, suggesting that the absence of CYLD causes aberrant neuronal activation. We found that this aberrant neuronal activation in the BLA of Cyld–/– mice may relate to the decreased excitability of principal neurons. Another possibility of aberrant neuronal activation could be the impaired excitatory synaptic transmission in the BLA of Cyld–/– mice. Specifically, both the frequency of spontaneous excitatory postsynaptic currents and the amplitude of miniature excitatory postsynaptic currents in BLA principal neurons were decreased. In addition, Cyld mutation caused an increase in both the frequency of miniature inhibitory postsynaptic currents in principal neurons and the number of parvalbumin+ interneurons, consistent with excessive local circuit inhibition in the BLA of Cyld–/– mice. Taken together, these results suggest that CYLD deficiency disrupts the neuronal activity and synaptic transmission in the BLA of mice which may contribute to the impaired fear memory observed in Cyld–/– mice.

Biocytin-Labeling in Whole-Cell Recording: Electrophysiological and Morphological Properties of Pyramidal Neurons in CYLD-Deficient Mice

“…The results implicate an in-built compensatory mechanism in CYLD-deficient mice, of which structural changes (spine loss) caused elevated R in and excitability in PNs [ 36 ]. It is worth noting that the finding of an increased number of APs in the PN of M1 differs from what we have observed in the BLA, where a reduced intrinsic excitability of the principal neurons occurred in the absence of CYLD [ 33 ]. Given that we observed, in the present study, a significantly increased R in , rise time of Aps, and decreased after the hyperpolarization (AHP) of the M1 PNs, which did not occur in the BLA [ 33 ], CYLD may regulate neuronal intrinsic property in a brain area and neuronal type specific manner.…”

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

“…Recent studies have shown a decrease in both the frequency of spontaneous excitatory postsynaptic currents and the amplitude of mEPSCs in principal neurons in the basolateral amygdala of Cyld −/− mice ( Li et al, 2021 ). Similarly, we found that the amplitudes of both mEPSCs and AMPAR-mediated eEPSCs were reduced in Cyld −/− MSNs compared to Cyld +/+ MSNs, suggesting a decrease in AMPAR levels at synapses.…”

“…In addition, mouse hippocampal neurons transfected with CYLD M719V show a significantly increased cytoplasmic localization of transactivator regulatory DNA-binding protein 43 (TDP-43) and decreased axonal length ( Dobson-Stone et al, 2020 ). CYLD deficiency causes impaired fear memory, auditory neuropathy, and cognitive inflexibility ( Li et al, 2021 ; Yang et al, 2021 ; Zajicek et al, 2022 ).…”

CYLD in health and disease

“…These behavioural phenotypes are correlated with reductions in hippocampal network excitability, long-term potentiation and pyramidal neuron spine numbers ( Colombo et al, 2021 ). Additionally, Cyld knockout impairs amygdala-dependent tone-cued fear memory, as Cyld −/− mice exhibit disrupted neuronal activity and synaptic transmission in the basolateral amygdala and a concomitant impaired fear memory ( Li et al, 2021b ). Cyld knockout mice also have a mild hearing impairment, or auditory neuropathy, perhaps associated with reduced neurite outgrowth ( Yang et al, 2021 ).…”