Hyperexcitable and immature-like neuronal activity in the auditory cortex of adult rats lacking the language-linked CNTNAP2 gene

Abstract

The contactin-associated protein-like 2 gene, CNTNAP2, is a highly penetrant risk gene thought to play a role in the genetic etiology of language-related disorders, such as autism spectrum disorder and developmental language disorder. Despite its candidacy for influencing language development, few preclinical studies have examined the role of CNTNAP2 in auditory processing. Using in vivo and in vitro electrophysiological recordings in a rat model with translational validity, we report that a loss of the Cntnap2 gene function caused immature-like cortical evoked potentials, delayed multiunit response latencies to acoustic stimuli, impaired temporal processing, and led to a pattern of hyperexcitability in both multiunit and single cell recordings in adulthood. These collective results provide direct evidence that a constitutive loss of Cntnap2 gene function in rats can cause auditory processing impairments similar to those seen in language-related human disorders, indicating that its contribution in maintaining cortical neuron excitability may underlie the cortical activity alterations observed in Cntnap2−/− rats.

Auditory processing in rodent models of autism: a systematic review

“…A higher frequency of mEPSPs than mIPSPs compared to WTs has been observed in A1 of VPA mice, Ehmt1 +/− mice and Pten conditional knockout mice, indicating underlying hypersensitivity of the AC [87,90,150]. The evoked firing rate is decreased in Shank3 +/− rats, VPA rats, and Fmr1 −/− rats, but increased in Mecp2 +/− and Cntnap2 -/− rats, Fmr1 −/− mice (particularly in layers 2/3), and Mecp2 overexpressing mice [28,30,32,33,117,123,146,152]. Interestingly, in vivo studies in VPA rats show no change in evoked firing rate to a simple 5-kHz tone, but decreased firing rates to human speech sounds, which fits with the patterns of evoked activity measured by fMRI in humans with autism [7,28,29,47].…”

“…P2 Mixed results are also visible in the amplitude of the P2 peak, with awake mice again mostly showing increased or unchanged amplitudes [48,55,60,64,67,147]. Anaesthetised rats and mGluR5 −/− interneuron mice on a C57BL/6 background have decreased P2 amplitudes, with the exception of Cntnap2 −/− rats [8,28,30,31,123]. N2 and P3 amplitudes are not included in Table 2 as few studies reported them, but they were found to be decreased in anaesthetised rat Fmr1 −/− and Mecp2 +/− models, similarly to P2 [30,32].…”

“…In cases where more than one study examined the same model, the most common result is indicated by bold font. It should be noted that a subset of these studies measured ERPs in anaesthetised animals [28,30,32,60,70,123]. Anaesthesia has been shown to disrupt auditory and other sensory event-related potentials [5,114].…”

“…The increase seen in the mice resembles the auditory endophenotype of people with FXS. The amplitude of the N1 peak in other models is variously increased, decreased, or unchanged [8,20,28,32,48,57,64,106,121,123]. Some of the increased and unchanged N1 amplitude results [8,57,64,106] come from studies in C57BL/6 mice over 3 months old, which may impede their ability to accurately portray an auditory endophenotype.…”

“…Electrophysiological recordings from the auditory cortex are more prevalent than from lower auditory structures. Results from these studies can vary, for example the spontaneous firing rate is decreased in Shank3 +/− and Cntnap2 −/− rat auditory cortex, but increased in Fmr1 −/− rat auditory cortex, and unchanged in ex vivo slice recordings from Fmr1 −/− mice [33,123,133,146]. Another measure of hyperexcitability is an increased ratio of mEPSPs to miniature inhibitory post-synaptic potentials (mIPSPs).…”