title: 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.
authors: Center for Neural Science, New York University, New York, New York, United States of America. vck1@nyu.edu
authors: Vibhakar C
authors: VC
authors: Kotak
authors: Anne E
authors: AE
authors: Takesian
authors: Patricia C
authors: PC
authors: MacKenzie
authors: Dan H
authors: DH
authors: Sanes
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology / Q000627:therapeutic use; D003051:Cochlea / Q000187:drug effects / Q000503:physiopathology; D058805:GABA Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D058785:GABA-A Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D005849:Gerbillinae / Q000502:physiology*; D034381:Hearing Loss / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000473:pathology*; D000077334:Zolpidem
chemical_list: D058805:GABA Uptake Inhibitors; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D001418:Baclofen