Rescue of inhibitory synapse strength following developmental hearing loss

Abstract

Inhibitory synapse dysfunction may contribute to many developmental brain disorders, including the secondary consequences of sensory deprivation. In fact, developmental hearing loss leads to a profound reduction in the strength of inhibitory postsynaptic currents (IPSCs) in the auditory cortex, and this deficit persists into adulthood. This finding is consistent with the general theory that the emergence of mature synaptic properties requires activity during development. Therefore, we tested the prediction that inhibitory strength can be restored following developmental hearing loss by boosting GABAergic transmission in vivo. Conductive or sensorineural hearing loss was induced surgically in gerbils prior to hearing onset and GABA agonists were then administered for one week. IPSCs were subsequently recorded from pyramidal neurons in a thalamocortical brain slice preparation. Administration of either a GABA(A) receptor a1 subunit specific agonist (zolpidem), or a selective GABA reuptake inhibitor (SGRI), rescued IPSC amplitude in hearing loss animals. Furthermore, this restoration persisted in adults, long after drug treatment ended. In contrast, a GABA(B) receptor agonist baclofen did not restore inhibitory strength. IPSCs could also be restored when SGRI administration began 3 weeks after sensory deprivation. Together, these results demonstrate long-lasting restoration of cortical inhibitory strength in the absence of normal experience. This suggests that in vivo GABA(A) receptor activation is sufficient to promote maturation, and this principle may extend to other developmental disorders associated with diminished inhibitory function.

Figure 1. Zolpidem or SGRI each rescue sIPSC strength in juveniles following P10 hearing loss.

A Representative spontaneous (s) IPSCs recorded in layers 2/3 (L2/3) pyramidal cells in ACx in slices from animals aged postnatal day (P) 18 to P22 (holding voltage, V_HOLD = −60 mV). Examples are shown from control (top left, black), CHL (bottom left, orange), zolpidem-treated CHL (top right, green), and SGRI-treated (bottom right, forest green) animals. B Bar graph (mean ± SEM) of average amplitude from all recorded neurons showing diminished sIPSC amplitude in CHL animals, and restoration of inhibitory strength after treatment with zolpidem or SGRI.

Figure 2. Rescue of inhibitory strength is evident for minimum evoked IPSCs.

A Representative traces of minimum-amplitude evoked IPSCs (me-IPSCs) recorded in L2/3 pyramidal cells in ACx in slices from animals aged postnatal day (P) 18 to P22 (V_HOLD =−60 mV). Examples are shown from control (top, black), CHL (second trace, orange). Zolpidem-treated CHL (third trace, green), and SGRI-treated CHL (bottom, forest green) animals. In each of these panels, the gray traces represent failures at sub-minimal stimulus intensities. B Bar graph (mean ± SEM) of average me-evoked IPSC amplitude from all recorded neurons showing diminished me-IPSC amplitude in CHL animals is rescued by treatment with zolpidem or SGRI.

Figure 3. Baclofen does not rescue inhibitory strength in juveniles after P10 hearing loss.

A Representative sIPSCs recorded in L2/3 pyramidal cells in ACx in slices from animals aged P18 to P22 (V_HOLD = −60 mV). Examples are shown from control (top, black), CHL (middle, orange), and BAC-treated CHL (bottom, olive) animals. B Bar graph (mean ± SEM) of average sIPSC amplitude from all recorded neurons showing diminished sIPSC amplitude in CHL animals is not rescued after treatment with BAC. C Representative traces of minimum-amplitude evoked IPSCs (me-IPSCs) recorded in L2/3 pyramidal cells in ACx in slices from animals aged postnatal day (P) 18 to P22 (V_HOLD =−60 mV). Examples are shown from control (top, black), CHL (middle, orange) and BAC-treated CHL (bottom, olive). In each of these panels, the gray traces represent failures at sub-minimal stimulus intensities. D Bar graph (mean ± SEM) of average me-evoked IPSC amplitude from all recorded neurons showing diminished me-IPSC amplitude in CHL animals is not rescued by treatment with BAC.

Figure 4. Rescue of inhibitory strength by zolpidem or SGRI persists in adults.

A Representative sIPSCs recorded in L2/3 pyramidal cells in ACx in slices from animals aged postnatal day (P) 90 to 110 (V_HOLD = −60 mV). Examples are shown from control (top left, black), CHL (bottom left, orange), zolpidem-treated CHL (top right, green), and SGRI-treated (bottom right, forest green) animals. B Bar graph (mean ± SEM) of average amplitude from all recorded neurons showing diminished sIPSC amplitude in CHL animals, and restoration of inhibitory strength after P11–17 treatment with zolpidem or SGRI.

Figure 5. Zolpidem rescues inhibitory strength following cochlear ablations.

A Representative sIPSCs recorded in L2/3 pyramidal cells in ACx in slices from animals aged postnatal day P18–22 (V_HOLD =−60 mV). Example traces are shown from control (top, black), SNHL (middle, red), and Zolpidem-treated (bottom, green) animals. B Bar graph (mean ± SEM) of average sIPSC amplitude from all recorded neurons showing diminished sIPSC amplitude in SNHL animals is rescued by treatment with Zolpidem.

Figure 6. Delayed SGRI intervention also rescues inhibitory strength in adults.

A Representative sIPSCs recorded in L2/3 pyramidal cells in ACx in slices from animals aged P90–110 (V_HOLD =−60 mV). Examples are shown from control (top, black), CHL (middle, orange), and SGRI-treated (bottom, forest green) animals. B Bar graph (mean ± SEM) of average sIPSC amplitude from all recorded neurons showing diminished sIPSC amplitude in adult CHL animals is rescued by P30–36 SGRI administration.