Title: Functional development of the retinogeniculate synapse
Description: During mammalian development, a tremendously complicated organism develops from a single cell. In the developing nervous system, proliferating multipotent precursors give birth to billions of neurons: not only different cell types, such as photoreceptors and ganglion cells, but huge numbers of each type. Since the number of cells is immense, and the number of connections formed by cells even larger, it is difficult to imagine how a mammalian brain could invariantly specify a single cell's identity based solely on that cell's lineage its gene expression pattern. Instead, both neural activity and molecular cues provide likely mechanisms by which precise circuits emerge from relative uniformity. Here, we examine the mouse visual system as a model for synaptic development, reviewing the role of sensory experience, spontaneous activity, and molecular mechanisms in establishing a functional visual circuit. First, we distinguish between the relative contributions of sensory experience and spontaneous activity in the maturation of the retinogeniculate synapse, using developmental changes in synaptic strength and synapse elimination as indicators of maturity. The bulk of maturation, including elimination of most afferents and a 50-fold strengthening, occurs over four days spanning eye-opening. However, only blockade of spontaneous retinal activity by tetrodotoxin, but not visual deprivation, prevents synaptic strengthening and inhibited pruning of excess retinal afferents. Our finding that spontaneous activity, not onset of vision, plays a crucial role in retinogeniculate development following eye-opening was stunningly confirmed using a mouse model of retinal degeneration (rd1) in which rod photoreceptors fail to develop properly.

Synapse remodeling becomes sensitive to changes in visual activity later in development, but only in animals with previous visual experience. Synaptic strengthening and pruning are disrupted by visual deprivation following one week of vision, but not by chronic deprivation from birth. We were unable to induce similar plasticity in the retinal degeneration mouse at this age. Thus, we conclude that spontaneous activity is necessary to drive the bulk of synaptic refinement in an early phase of synapse maturation, while sensory experience is important in a later phase for the maintenance of connections. We were intrigued that the visual deprivation-induced synaptic plasticity we observed occurs at the same age as the critical period for ocular dominance plasticity, though in thalamus this plasticity occurs within axons from the same retina, not separate eyes. Previous studies of deprivation in visual thalamus had shown much larger effects on receptive fields in primary visual cortex. Thus, we further characterized this sensitive period of retinogeniculate development. Sensitivity to visual deprivation peaks during a late period in development. Prior visual experience is required to induce synaptic plasticity in response to deprivation, as chronic dark rearing and dark rearing from three days following eye-opening do not cause the degree of excess afferentation and synaptic weakening observed in mice dark reared after a full week of visual experience. These changes take >7 days to occur, as animals studied only three days after late deprivation did not show the dramatic changes that animals deprived into maturity did. Furthermore, we reversed the effect of prior deprivation-induced changes on synapse strength and connectivity by restoring normal visual experience for >3 days. Thus, plasticity remains in the thalamus until at least p32, the latest age amenable to study in our slice preparation.

While these studies characterized the contributions of different presynaptic sources of activity to synaptic plasticity in thalamus, our experiments did not offer insight into the molecular mechanisms underlying these changes. One model which may help reveal distinct mechanisms underlying the early and late phases of synapse maturation observed at the retinogeniculate connection is the Stargazer mouse. This mouse model lacks the AMPAR trafficking protein Stargazin (Cacng2). Early synapse elimination proceeds normally in Stargazer mice, but more than two weeks after eye opening, synaptic strength is substantially weaker, and additional afferents have been recruited to LGN relay neurons. Although these mice are subject to disruption of normal activity patterns by frequent seizures, these effects do not seem to be due to changes in activity, as a separate mouse model with similar seizures, the Tottering mouse, shows relatively normal maturation of synaptic connectivity. Thus, we propose that proper trafficking of AMPA receptors is necessary for elimination of improper afferents and maintenance of appropriate connections.