Developmental hearing loss-induced perceptual deficits are rescued by genetic restoration of cortical inhibition

• 成果类型: Article
• 署名作者: Masri, Samer; Mowery, Todd M.; Fair, Regan; Sanes, Dan H.
• 署名单位: New York University; Rutgers University System; Rutgers University New Brunswick; New York University; New York University; New York University; NYU Langone Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8614
• DOI: 10.1073/pnas.2311570121
• 发表日期: 2024-06-11
• 关键词: postsynaptic gaba(b) receptors; auditory temporal resolution; gabaergic transmission; homeostatic plasticity; postnatal-development; psychometric function; transgene expression; amplitude-modulation; speech recognition; period

摘要

Even a transient period of hearing loss during the developmental critical period can induce long - lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these 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. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABA A , Gabra1 ; GABA B , Gabbr1b ) in pyramidal neurons, and an enzyme that mediates GABA synthesis ( GAD65 ) presynaptically in parvalbumin - expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABA B receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABA B receptor - dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.