PMID- 32402894 OWN - NLM STAT- MEDLINE DCOM- 20210823 LR - 20210823 IS - 1878-5891 (Electronic) IS - 0378-5955 (Linking) VI - 392 DP - 2020 Jul TI - Morphological and molecular correlates of altered hearing sensitivity in the genetically audiogenic seizure-prone hamster GASH/Sal. PG - 107973 LID - S0378-5955(20)30020-4 [pii] LID - 10.1016/j.heares.2020.107973 [doi] AB - Rodent models of audiogenic seizures, in which seizures are precipitated by an abnormal response of the brain to auditory stimuli, are crucial to investigate the neural bases underlying ictogenesis. Despite significant advances in understanding seizure generation in the inferior colliculus, namely the epileptogenic nucleus, little is known about the contribution of lower auditory stations to the seizure-prone network. Here, we examined the cochlea and cochlear nucleus of the genetic audiogenic seizure hamster from Salamanca (GASH/Sal), a model of reflex epilepsy that exhibits generalized tonic-clonic seizures in response to loud sound. GASH/Sal animals under seizure-free conditions were compared with matched control hamsters in a multi-technical approach that includes auditory brainstem responses (ABR) testing, histology, scanning electron microscopy analysis, immunohistochemistry, quantitative morphometry and gene expression analysis (RT-qPCR). The cochlear histopathology of the GASH/Sal showed preservation of the sensory hair cells, but a significant loss of spiral ganglion neurons and mild atrophy of the stria vascularis. At the electron microscopy level, the reticular lamina exhibited disarray of stereociliary tufts with blebs, loss or elongated stereocilia as well as non-parallel rows of outer hair cells due to protrusions of Deiters' cells. At the molecular level, the abnormal gene expression patterns of prestin, cadherin 23, protocadherin 15, vesicular glutamate transporters 1 (Vglut1) and -2 (Vglut2) indicated that the hair-cell mechanotransduction and cochlear amplification were markedly altered. These were manifestations of a cochlear neuropathy that correlated to ABR waveform I alterations and elevated auditory thresholds. In the cochlear nucleus, the distribution of VGLUT2-immunolabeled puncta was differently affected in each subdivision, showing significant increases in magnocellular regions of the ventral cochlear nucleus and drastic reductions in the granule cell domain. This modified inputs lead to disruption of Vglut1 and Vglut2 gene expression in the cochlear nucleus. In sum, our study provides insight into the morphological and molecular traits associated with audiogenic seizure susceptibility in the GASH/Sal, suggesting an upward spread of abnormal glutamatergic transmission throughout the primary acoustic pathway to the epileptogenic region. CI - Copyright (c) 2020 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Sanchez-Benito, David AU - Sanchez-Benito D AD - Institute of Neuroscience of Castilla y Leon (INCYL), University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain. FAU - Hyppolito, Miguel A AU - Hyppolito MA AD - Laboratory of Neurobiology of Hearing, Department of Ophthalmology, Otorhinolaryngology, Head and Neck Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. FAU - Alvarez-Morujo, Antonio J AU - Alvarez-Morujo AJ AD - Institute of Neuroscience of Castilla y Leon (INCYL), University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Department of Human Anatomy and Histology, Faculty of Medicine, University of Salamanca, Salamanca, Spain. FAU - Lopez, Dolores E AU - Lopez DE AD - Institute of Neuroscience of Castilla y Leon (INCYL), University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Department of Cell Biology and Pathology, Faculty of Medicine, University of Salamanca, Salamanca, Spain. FAU - Gomez-Nieto, Ricardo AU - Gomez-Nieto R AD - Institute of Neuroscience of Castilla y Leon (INCYL), University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Department of Cell Biology and Pathology, Faculty of Medicine, University of Salamanca, Salamanca, Spain. Electronic address: richard@usal.es. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200426 PL - Netherlands TA - Hear Res JT - Hearing research JID - 7900445 RN - 0 (Vesicular Glutamate Transport Protein 1) RN - 0 (Vesicular Glutamate Transport Protein 2) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - *Auditory Threshold MH - *Behavior, Animal MH - Cochlea/metabolism/*physiopathology/ultrastructure MH - Cricetinae MH - Disease Models, Animal MH - Epilepsy, Reflex/genetics/metabolism/*physiopathology/psychology MH - Epilepsy, Tonic-Clonic/genetics/metabolism/*physiopathology/psychology MH - Glutamic Acid/metabolism MH - *Hearing MH - Male MH - Noise MH - Vesicular Glutamate Transport Protein 1/genetics/metabolism MH - Vesicular Glutamate Transport Protein 2/genetics/metabolism OTO - NOTNLM OT - Animal models of epilepsy OT - Audiogenic seizures OT - Cochlear neuropathy OT - Cochlear nucleus OT - Spiral ganglion neurons OT - VGLUT COIS- Declaration of competing interest The authors declare no competing interests. EDAT- 2020/05/14 06:00 MHDA- 2021/08/24 06:00 CRDT- 2020/05/14 06:00 PHST- 2020/01/08 00:00 [received] PHST- 2020/03/30 00:00 [revised] PHST- 2020/04/07 00:00 [accepted] PHST- 2020/05/14 06:00 [pubmed] PHST- 2021/08/24 06:00 [medline] PHST- 2020/05/14 06:00 [entrez] AID - S0378-5955(20)30020-4 [pii] AID - 10.1016/j.heares.2020.107973 [doi] PST - ppublish SO - Hear Res. 2020 Jul;392:107973. doi: 10.1016/j.heares.2020.107973. Epub 2020 Apr 26.