Impaired subcortical processing of amplitude-modulated tones in mice deficient for Cacna2d3, a risk gene for autism spectrum disorders in humans

Abstract

Temporal processing of complex sounds is a fundamental and complex task in hearing and a prerequisite for processing and understanding vocalization, speech, and prosody. Here we studied response properties of neurons in the inferior colliculus (IC) in mice lacking Cacna2d3, a risk gene for autism spectrum disorders. The α₂δ3 auxiliary Ca²⁺ channel subunit encoded by Cacna2d3 is essential for proper function of glutamatergic synapses in the auditory brainstem. Recent evidence has shown that much of auditory feature extraction is performed in the auditory brainstem and IC, including processing of amplitude modulation (AM). We determined both spectral and temporal properties of single- and multi-unit responses in the IC of anesthetized mice. IC units of α₂δ3^-/- mice showed normal tuning properties yet increased spontaneous rates compared with α₂δ3^+/+. When stimulated with AM tones, α₂δ3^-/- units exhibited less precise temporal coding and reduced evoked rates to higher modulation frequencies (f_m). Whereas first spike latencies (FSL) were increased for only few modulation frequencies, population peak latencies were increased for f_m ranging from 20 Hz to 100 Hz in α₂δ3^-/- IC units. The loss of precision of temporal coding with increasing f_m from 70 Hz to 160 Hz was characterized using a normalized offset-corrected (Pearson-like) correlation coefficient, which appeared more appropriate than the metrics of vector strength. The processing deficits of AM sounds analyzed at the level of the IC indicate that α₂δ3^-/- mice exhibit a subcortical auditory processing disorder. Similar deficits may be present in other mouse models for autism spectrum disorders.

Significance statement

Human speech and animal vocalization contain amplitude-modulated (AM) sounds. Perception of AM sounds requires correct processing of auditory signals in cochlea, auditory brainstem and the inferior colliculus (IC). We have analyzed the ability of IC neurons (units) to extract AM sounds in mice lacking the Cacna2d3 gene encoding the α₂δ3 subunit of voltage-activated calcium channels, which are important for proper function of excitatory synapses. With increasing modulation frequencies, units of α₂δ3^-/- mice showed reduced evoked activity, less precise temporal coding, and longer response latencies compared with units of α₂δ3^+/+ mice. Humans lacking Cacna2d3 exhibit genetic autism, a neurodevelopmental disorder often accompanied by impaired auditory processing. We propose Cacna2d3 as a candidate gene linking an auditory processing disorder with genetic autism.