Integration of GABAergic transmission in the vestibulo-thalamic circuit regulates the maturation of spatial navigation

Abstract

Foraging and homing behaviors of animals require navigational clues. In rodents, accurate transition of vestibular cues into a framework of spatial orientations in the brain has been shown to play a crucial role in spatial navigation. To understand how spatial information is represented and shaped in the vestibulo-thalamic circuitry during postnatal development, the role the GABAergic transmission within the neonatal vestibular nucleus (VN) in the formation of spatial map in adults remains elusive.

Using retrograde tracing, we confirmed structural connectivity from VN to the thalamus, the gateway of the ascending vestibular pathway to the cerebral cortex. Using expression of Fos protein as a marker for neuronal activation by specific sensory input, we observed a topographic organization of vestibular inputs in the thalamus of rats subjected to three-dimensional sinusoidal wobble rotation. In response to counterclockwise and clockwise rotations, Fos-immunoreactive neurons in thalamic subnuclei on either side of the brain showed symmetric distribution. Interestingly, Fos-immunoreactive neurons in the beta nucleus and subnucleus B of the inferior olive exhibited asymmetric distribution to wobble rotation in one direction.

We previously found that GABAergic VN synapses between postnatal day (P) 3 and 14 exhibited a progressive change in long-term depression of GABAA receptor-mediated evoked-postsynaptic current. Based on this observation, we further investigated the role of GABAergic transmission in the VN on the maturation of spatial representation in the thalamus. We used a polymer implant to allow slow delivery of GABAA receptor antagonist, bicuculline, to the underlying VN to observe long-term consequences in thalamic topographic representation and navigational behavior in adults.

We found that adult rats pre-treated with bicuculline at P1 exhibited a deranged vestibular-related spatial map in the thalamus. That Fosimmunoreactive thalamic neurons were significantly enhanced in these adult rats demonstrate that a balanced GABAergic transmission in the neonatal VN is crucial for maintaining a normal topographic spatial organization in the adult thalamus for the integration of sensory information. These adult rats also showed deficiencies in dead reckoning, a foraging and homing behavioral task that requires vestibular inputs. Comparable deficits were also observed in control rats with selective lesion of vestibular-related thalamic subnuclei. Notably, adult rats pre-treated with bicuculline at P14 showed no change in spatial map and navigation behavior.

Altogether, our data indicate that GABAergic transmission in the VN during a postnatal critical period is crucial for establishing a functional neural circuitry for spatial reference and spatial navigation at the adult stage. These results provide basis for the development of therapeutic strategies in treating learning impairments in vestibular-disoriented children.