Abstract
Brain development and learning is accompanied by morphological and molecular changes in neurons. The growth associated protein 43 (Gap43), indicator of neurite elongation and synapse formation, is highly expressed during early stages of development. Upon maturation of the brain, Gap43 is down-regulated by most neurons with the exception of subdivisions such as the CA3 region of hippocampus, the lateral superior olive (LSO) and the central inferior colliculus (CIC). Little is known about the regulation of this mRNA in adult brains. We found that the expression of Gap43 mRNA in specific neurons can be modulated by changing sensory activity of the adult brain. Using the central auditory system of rats as a model, Gap43 protein and mRNA levels were determined in LSO and CIC of hearing-experienced rats unilaterally or bilaterally deafened or unilaterally stimulated by a cochlear implant (CI). Our data indicate that Gap43 is a marker useful beyond monitoring neuronal growth and synaptogenesis, reflecting also specific patterns of synaptic activities on specific neurons. Thus, unilateral loss of input to an adult auditory system directly causes asymmetrical expression of Gap43 mRNA between LSOs or CICs on both sides of the brainstem. This consequence can be prevented by simple-patterned stimulation of a dysfunctional ear by way of a CI. We suggest that as a function of input balance and activity pattern, Gap43 mRNA expression changes as cells associate converging afferent signals.
Highlights
In the auditory system of the adult mammalian brain, FBJ osteosarcoma oncogene fos is one of the first genes activated by sensory activity evoked either by acoustical or electrical intracochlear stimulation (EIS) [1,2]
Neurons throughout lateral superior olive (LSO) (Fig. 4A, B) and in the ventral part of CIC (Fig. 5A, B) possessed a notable level of growth associated protein 43 (Gap43) mRNA in their cytoplasm (Figs. 4D, 5D inset), showing a mean staining intensity of 4.5660.42 for LSO (Fig. 6B) and 0.6660.041 for CIC (Fig. 6D), both against 0 for the mean staining level obtained by using the sense probe (Figs. 4A, B, 5E, F insets)
Unlike controls and LSOi of ud rats, the mean staining intensity of Gap43 mRNA positive neurons was bilaterally increased for all stimulation times (n = 25/ 117 rats/slices; us i: 8.9160.66; us c: 8.7260.62; ud i: 4.1760.32; Co: 4.5660.42; p,0.001 for all; Figs. 6B, 7B)
Summary
In the auditory system of the adult mammalian brain, FBJ osteosarcoma oncogene fos ( known as c-fos) is one of the first genes activated by sensory activity evoked either by acoustical or electrical intracochlear stimulation (EIS) [1,2]. AP-1 triggers the expression of many genes, among them the growth associated protein Gap43 [4] This phosphoprotein is neuron-specific and expressed in neuronal somata, axons, and growth cones during pre- and early postnatal development [5,6]. Using Gap gene silencing in the olivo-cerebellar system, Gap is shown to be essential for maintenance of climbing fiber structure and to promote sprouting after lesion of the inferior olive [11,12]. Overall, these studies provide evidence that Gap is crucial for neuronal network formation
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