Abstract
The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.
Highlights
The inferior colliculus (IC) plays an important role in auditory processing and integrating information about the spectral, temporal, and spatial features of sound that has been preprocessed by multiple specialized brainstem networks [1,2]
Our results suggest that the defects of auditory processing in the IC of the transgenic mice (Tg) mice were primarily caused by impaired inhibitory signaling
Of the Tg mice were primarily caused by impaired inhibitory signaling. This agrees with our previous report of increased inhibition in the brain of the Tg mice resulting in hyperactivity, which was successfully reduced by the administration of a non-competitive channel blocker for the GABA receptor chloride channels [22]
Summary
The inferior colliculus (IC) plays an important role in auditory processing and integrating information about the spectral, temporal, and spatial features of sound that has been preprocessed by multiple specialized brainstem networks [1,2]. The IC is morphologically divided into the core (central nucleus) and shell (dorsal and external nucleus) subdivisions. The central nucleus is tonotopically organized, receives ascending auditory inputs from the brainstem auditory nuclei, and projects to the thalamus, from where the auditory signal proceeds to the cortex. The IC shell plays a neuromodulatory role, receiving and processing ascending auditory information, and descending projections from the auditory cortex (targeting mainly dorsal nucleus [3]), and inputs from the IC core and nonauditory structures (external nucleus [4]). IC neurons are represented by two major classes, excitatory glutamatergic neurons and inhibitory GABAergic neurons. GABAergic neurons comprise about 20–30% of the inhibitory neurons in the IC of rodents [5–8], and 15% in the human IC [9]. Despite the lower proportion of GABAergic cells in the IC, inhibition plays a critical role in shaping IC neuronal responses [10]
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