Preserving Inhibition during Developmental Hearing Loss Rescues Auditory Learning and Perception

Abstract

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory CNS. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABA A and GABA B receptor-mediated IPSPs in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes; but when administered after the critical period, it only restored GABA B receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate ␣1 subunitdependent GABA A responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABA A and GABA B IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented.

Stability in the Face of Change: Lifelong Experience-Dependent Plasticity in the Sensory Cortex

“…However, lasting changes in the dynamics of inhibitory synapses after sensory deprivation may be circuit dependent. In the A1, developmental hearing loss can induce enduring disinhibition and behavioral deficits that can be improved by restoring the inhibitory tone (Mowery et al, 2019), whereas visual deprivation triggers circuit-specific changes in the V1 that can result in increased inhibitory tone in local cortical circuits (Maffei et al, 2006;Kannan et al, 2016;Miska et al, 2018). While it is still unclear if these differences stem from distinct mechanisms of homeostasis in response to sensory manipulations, studies agree that the fast dynamics of inhibitory neurotransmission may be the key to sensory adaptations during the critical periods (Gainey and Feldman, 2017).…”

Early Sensory Deprivation Leads to Differential Inhibitory Changes in the Striatum During Learning

“…Up or downregulation of GABAA-α1 containing receptors has previously been shown to govern mature forms of inhibitory synaptic transmission (Fritschy et al, 1994;Heinen et al, 2004;Bosman et al, 2005). Hence, restoration of GABAergic inhibition in cases of behavioral deficits could be a valuable target to investigate for potential therapy approaches (Verret et al, 2012;Schmid et al, 2016;Dargaei et al, 2018;Mowery et al, 2019).…”

Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition

“…Also, cochlear ablation prior to hearing onset (Sanes et al, 1992) or deafness in the deafness (dn/dn) mutant mouse (Oleskevich and Walmsley, 2002) led to larger EPSP amplitudes and lower inhibitory synaptic strength. This phenomenon was observed in the cochlear nucleus (Oleskevich and Walmsley, 2002), in the lateral lemniscus, and in IC neurons (Sanes et al, 1992), as well as in thalamocortical and intracortical primary auditory cortex neurons (Kotak et al, 2005(Kotak et al, , 2013Mowery et al, 2019). It was suggested that the larger EPSP amplitudes in congenital deafness may result from an increase in AMPA-and non-NMDA receptors and a decrease in inhibitory postsynaptic potential conductance.…”

“…Imbalances in excitation and inhibition are observed in acquired deafness, which can be caused by cochlear damage, middle-ear ossicle removal, acoustic trauma, or drug-induced deafness ( Kotak et al, 2013 ; Mowery et al, 2019 ). In previous studies, it was shown that acquired deafness in mature animals led to hyperexcitability that coincided with a decrease in GABA and glutamic acid decarboxylase (GAD65) ( Bledsoe et al, 1995 ; Abbott et al, 1999 ).…”