Developmental hearing loss-induced perceptual deficits are rescued by cortical expression of GABAB receptors

Abstract

Even transient periods of developmental hearing loss during the developmental critical period have been linked to long-lasting deficits in auditory perception, including temporal and spectral processing, which correlate with speech perception and educational attainment. In gerbils, hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABA_A and metabotropic GABA_B receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABA_A receptors. We developed viral vectors to express both endogenous GABA_A or GABA_B receptor subunits in auditory cortex and tested their capacity to restore perception of temporal and spectral auditory cues following critical period hearing loss in the Mongolian gerbil. HL significantly impaired perception of both temporal and spectral auditory cues. While both vectors similarly increased IPSCs in auditory cortex, only overexpression of GABA_B receptors improved perceptual thresholds after HL to be similar to those of animals without developmental hearing loss. These findings identify the GABA_B receptor as an important regulator of sensory perception in cortex and point to potential therapeutic targets for developmental sensory disorders.

Keywords: GABAA; GABAB; auditory cortex; auditory perception; hearing loss; synaptic inhibition.

Figure 1:. Viral vector design and validation.

(A) For both Gabra1 and Gabbr1b AAVs, primary auditory cortex layer 2/3 was injected (Nanoject 2; Drummond) with approximately 250 nl of virus. After three weeks of expression a thalamocortical slice preparation was made and whole cell recordings (current clamp) from ACx L2/3 pyramidal cells were carried out. (B) Top, Diagram showing Gabra1 vector. Bottom, micrograph from ACx L2/3 showing Gabra1 infected cells (fluorescing, mCh) and one patched pyramidal neuron. (C) Representative evoked IPSP showing the larger GABAA potential in the Gabra1 infected pyramidal neuron (fluorescing patched cell from B) vs local uninfected (non-fluorescing) pyramidal neuron from the same slice. D) Plot diagram showing the average difference in GABA_A IPSP amplitudes for uninfected versus Gabra1 infected pyramidal neurons. (E) Top, Diagram showing Gabbr1b vector. Bottom, micrograph from ACx L2/3 showing Gabbr1b infected cells (fluorescent, mCh) and one patched pyramidal neuron. (F) Representative evoked IPSP showing the larger GABA_B potential in the Gabbr1b infected pyramidal neuron (fluorescing patched cell from C) vs local uninfected (non-fluorescing) pyramidal neuron from the same slice. (G) Plot diagram showing the average difference in GABA_B IPSP amplitudes for uninfected versus Gabb0r1b infected pyramidal neurons.

Figure 2:. Experimental paradigm.

(A) The experimental timeline, and each of the experimental groups is shown. (B) Example stimulus waveforms are shown for the AM depth detection task (top) and the SM depth detection task (bottom). (C) The Go-Nogo paradigm used for psychometric testing is shown.

Figure 3:. Gabbr1b expression restores AM detection.

(A) Representative behavior for a HL-reared gerbil expressing Gabbr1b (HL+Gabbr1b) and a HL-reared gerbil expressing GFP (HL+GFP) in AC, both tested after transient hearing loss (HL). (B) AM depth thresholds achieved by each group over training days. Mean ± SEM. (C) Gabbr1b expression in AC rescued AM perception relative to GFP expression on day 1 of psychometric testing. Bars indicate significant differences (see text for statistical values). (D) Gabbr1b expression in AC rescued AM perception relative to GFP expression on day 7 of psychometric testing. Bars indicate significant differences (see text for statistical values).

Figure 4:. Gabbr1b expression restores SM detection.

(A) Example psychometric curves of individual gerbils showing d’ at each of the 5 modulation depths presented in a single session. The leftward shift of the HL+Gabbr1b function, relative to HL+GFP function indicates improved performance. Bars indicate significant differences (see text for statistical values). (B) Group performance on each day of psychometric testing. (C) There are no differences in SM modulation thresholds on the first day of psychometric testing, as calculated by fit crossing d’ = 1. (D) SM thresholds on day 7 of psychometric testing. Both HL+Gabbr1b and NH+GFP groups performed significantly better than HL+GFP animals. Bars indicate significant differences (see text for statistical values).