Maturation profile of GABA-ergic inhibition in the vestibular nucleus : role in developmental plasticity and spatial recognition

Abstract

Inhibitory synaptic transmission within the vestibular circuits plays an essential

regulatory role in coordinating vestibular functions. The maturation profile of γ-

aminobutyric acid (GABA) synapses in the vestibular system remains unknown. To

address this, we first used double immunohistochemistry to document the postnatal

expression profile of GABAA receptors in canal-related and saccule-related vestibular

nuclear neurons of rats. The proportion of Fos / GABAA receptors α1 subunit doublelabeled

neurons progressively increased with age. Whole-cell patch-clamp experiments

on brainstem slice preparations were also employed to characterize the developmental

properties of these synapses within the medial vestibular nucleus. The frequency of

GABAA receptor-mediated miniature inhibitory postsynaptic currents (IPSC)

progressively increased during the first two postnatal weeks and reached a plateau

thereafter. This is in agreement with an increase in sensitivity to GABAA receptor α1

subunit agonist zolpidem during the same period. The rise time and decay time however

decreased by 2-fold. These results suggest that change in the composition of GABAA

receptor occurs during the functional maturation of medial vestibular neurons.

To further investigate whether GABA receptors contribute to synaptic plasticity in

the developing vestibular nucleus, two stimulus protocols were used. Repetitive

depolarizing pulses induced long-lasting decrease in the frequency of GABAA receptormediated

spontaneous IPSCs between P3 and P7. The probability of inducing such

frequency decline of sIPSCs decreased after the first postnatal week. High frequency

stimulation on the other hand, induced long-term depression (LTD) of GABAA receptormediated

evoked IPSCs between P3 and P5. The probability of inducing LTD decreased

after P14. These results indicate that LTD at GABAergic synapses could be easily

induced in developing medial vestibular neurons before maturation of GABAergic

synaptic transmission.

To examine if GABAergic transmission within the vestibular nucleus is crucial

for establishment of gravity-related spatial organization, an intervention approach was

adopted to perturb GABAergic transmission within the postnatal vestibular nucleus. A

slice of Elvax loaded with either GABAA receptor agonist muscimol or antagonist

bicuculline was inserted into the fourth ventricle and covered the bilateral vestibular

nuclei at different ages. Expression of Fos protein in functionally activated neurons was

used to demarcate the topographic spatial map in the inferior olive. The spatial map in

subnuclei IOβ and DMCC was disturbed in each adult rat that was implanted with

bicuculline- or muscimol-loaded Elvax at P1. However, no change was observed in

adult rats that were pretreated with bicuculline or muscimol at P14 or P21. Vestibularrelated

behavior tests were also performed. The acquisition of negative geotaxis, an

otolith-related orientation reflex, was delayed in postnatal rats pretreated with bicuculline

but was advanced in those rats pretreated with muscimol. Furthermore, the acquisition of

motor learning, evaluated by rotarod test, was impaired in adult rats treated with

bicuculline or muscimol.

Taken together, our results indicated that maturation of GABAergic transmission

within the vestibular nucleus play important roles in development of spatial recognition

and vestibular-related behavior.