Introduction spontaneous nystagmus SN, yaw head tilt YHT and roll

Brain Research 882 2000 45–54 www.elsevier.com locate bres Research report The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig a a , b a Andrew J. Sansom , Paul F. Smith , Cynthia L. Darlington , Richard Laverty a Vestibular Research Group , Department of Pharmacology, School of Medical Sciences, University of Otago Medical School and Neuroscience Research Centre , University of Otago, Dunedin, New Zealand b Vestibular Research Group , Department of Psychology, School of Medical Sciences, University of Otago Medical School and Neuroscience Research Centre , University of Otago, Dunedin, New Zealand Accepted 2 August 2000 Abstract Previous studies have demonstrated that vestibular compensation, the process of behavioural recovery which occurs following unilateral deafferentation of the vestibular labyrinth UVD, is correlated with changes in in vitro phosphorylation of various protein substrates in the brainstem vestibular nucleus complex VNC. The aim of the present study was to investigate the possible causal relationship between protein kinase activity and the induction of the vestibular compensation process, by delivering inhibitors of protein kinase C PKC or 21 Ca calmodulin-dependent kinase II CaMKII into the ipsilateral VNC at the time of the UVD and determining their effects on three static symptoms of UVD, spontaneous nystagmus SN, yaw head tilt YHT and roll head tilt RHT in guinea pigs. Infusion of the PKC inhibitor, 3-[1-3-dimethylaminopropyl-1H-indol-3-yl]-4-1H-indol-3-yl-1H-pyrrole-2,5-dione, HCl bisindolylmaleimide I, HCl GF 109203X, HCl ‘Bis I’, at a concentration of 5 or 50 mM, significantly increased SN frequency at the earliest time points 6 and 8 h post-UVD compared to vehicle controls and the less selective analogue, 2,3-bis1H-indol-3-yl-N-methylmaleimide bisindolylmaleimide V ‘Bis V’. However, the compensation of YHT and RHT was unaffected by the PKC inhibitor. By contrast, the cell-permeable CaMKII inhibitor, myristoylated autocamtide-2 related inhibitory peptide N-Myr-Lys-Lys-Ala-Leu-Arg-Arg-Gln-Glu-Ala-Val-Asp-Ala-Leu-OH ‘myr-AIP’ or the cell-impermeable analogue, autocamtide-2 related inhibitory peptide N-Lys-Lys-Ala-Leu-Arg-Arg-Cln-Glu-Ala-Val- Asp-Ala-Leu-OH ‘AIP’, failed to alter the compensation of SN, YHT or RHT at any dose compared to vehicle controls. These results implicate PKC-, but not CaMKII-, signal transduction pathways in the initiation of SN compensation in guinea pig.  2000 Elsevier Science B.V. All rights reserved. Theme : Sensory systems Topic : Auditory, vestibular, and lateral line: periphery 21 Keywords : Protein kinase C; Vestibular compensation; Ca calmodulin-dependent kinase II; Vestibular nuclei; Neural plasticity

1. Introduction spontaneous nystagmus SN, yaw head tilt YHT and roll

head tilt RHT] and therefore relate to the imbalance in Unilateral deafferentation of the peripheral vestibular resting activity between neurons in the ipsilateral and labyrinth UVD results in a complex syndrome of eye contralateral vestibular nucleus complexes VNC. The movement and postural disorders which arises from the dynamic symptoms are those which are observed during imbalance in tonic and dynamic neuronal activity in the head movement [e.g., reduced gain of the vestibulo-ocular vestibulo-ocular and vestibulo-spinal reflex pathways [43]. reflex VOR] and are related to the reduced sensitivity of The static symptoms of UVD have been referred to as VNC neurons to head movement stimuli see Ref. [6] for a those which persist in the absence of head movement [e.g., review. Over time, the severity of some static symptoms gradually decreases in a process of behavioural recovery known as ‘vestibular compensation’. Although a partial Corresponding author. Tel.: 164-3-479-5747; fax: 164-3-479-5747 recovery of resting activity in the VNC ipsilateral to the or 9140. E-mail address : paul.smithstonebow.otago.ac.nz P.F. Smith. UVD ipsi-VNC is believed to be largely responsible for 0006-8993 00 – see front matter  2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 7 8 6 - 4 46 A the compensation of the static symptoms, the biochemical selective CaMKII inhibitor was not employed. The present basis of this resting activity recovery, and the other experiment attempted to further investigate the role of neuronal changes responsible for compensation, are poorly protein kinases in static compensation by comparing the understood see Refs. [6,38] for a review. effects of PKC and CaMKII inhibitors, delivered into the 21 Protein kinase C PKC and Ca calmodulin-depen- ipsi-VNC at the time of the UVD in guinea pig. dent kinase II CaMKII are major serine threonine pro- tein kinases found in particularly high concentrations in brain [42]. There is good evidence that these kinases play

2. Methods