William Guido

The cAMP-response element-binding protein (CREB) plays an important role in visual cortical plasticity that follows the disruption of sensory activity, as induced by dark rearing (DR). Recent findings indicate that the dorsal lateral geniculate nucleus (dLGN) of thalamus is also sensitive to altered sensory activity. DR disrupts retinogeniculate synaptic strength and pruning in mice, but only when DR starts one week after eye opening (delayed DR, DDR) and not after chronic DR (CDR) from birth. While DR upregulates CREB in visual cortex, whether it also modulates this pathway in dLGN remains unknown. Here we investigate the role of CREB in the dLGN of mice that were CDR or DDR using western blot and immunofluorescence. Similar to findings in visual cortex, CREB is upregulated in dLGN after CDR and DDR. These findings are consistent with the proposal that DR up-regulates the CREB pathway in response to decreased visual drive.

A fundamental feature of the mammalian visual system is the presence of separate channels that work in parallel to efficiently extract and analyze specific elements of a visual scene. Despite the extensive use of the mouse as a model system, it is not clear whether such parallel organization extends beyond the retina to subcortical structures, such as the dorsal lateral geniculate (dLGN) of thalamus. To begin to address this, we examined the morphology of biocytin-filled relay cells recorded in dLGN of mice. Based on a quantitative assessment of their dendritic architecture, we found that even at early postnatal ages relay cells could be readily classified as X-like (biconical), Y-like (symmetrical), or W-like (hemispheric) and that each cell type was regionally specified in dLGN. X-like cells were confined primarily to the monocular ventral region of dLGN. Y-like cells occupied a central core that also contained ipsilateral eye projections, whereas W-like cells were found along the perimeter of dLGN. Similar to cat, Y-like cells were more prevalent than X- and W-like cells, and X-like cells tended to be smaller than other cell types. However, the dendritic fields of X- and W-like cells did not exhibit an orientation bias with respect to optic tract or boundaries of dLGN. Although we found clear morphological differences among relay cells, an analysis of their electrophysiological properties did not reveal any additional distinguishing characteristics. Overall, these data coupled with recent observations in the retina suggest that the mouse has many of the hallmark features of a system-wide parallel organization.

Monocular deprivation (MD) is a classic paradigm for experience-dependent cortical plasticity. One form is known as homeostatic plasticity, in which neurons innervated by the deprived eye show a remarkable capacity to compensate for degraded visual signals in an attempt to stabilize network activity. Although the evidence supporting homeostatic plasticity in visual cortex is extensive, it remains unclear whether neurons in subcortical visual structures respond to MD in a similar manner. Here we examined whether cells in the dorsal lateral geniculate nucleus (dLGN), the thalamic relay between the retina and visual cortex, show similar forms of experience-dependent homeostatic plasticity following MD. Two-week-old mice were monocularly deprived for a period of 5–7 d and miniature EPSCs (mEPSCs) were obtained from cells located in dLGN regions receiving input from the deprived or nondeprived eye. We found that MD promotes increases in the frequency and amplitude of mEPSCs and were restricted to the monocular segment contralateral to the deprived eye. These changes were accompanied by an increase in the probability of glutamate release at corticothalamic terminals that arise from the deprived visual cortex. Our findings indicate that homeostatic synaptic regulation from MD extends beyond cortical circuitry and shed light on how the brain modulates and integrates activity in the face of altered sensory experience.

Background: Most retinal ganglion cells (RGCs) convey contrast and motion information to visual brain centers. Approximately 2% of RGCs are intrinsically photosensitive (ipRGCs), express melanopsin and are necessary for light to modulate specific physiological processes in mice. The ipRGCs directly target the suprachiasmatic nucleus (SCN) to photoentrain circadian rhythms, and the olivary pretectal nucleus (OPN) to mediate the pupillary light response. How and when this ipRGC circuitry develops is unknown. Results: Here, we show that some ipRGCs follow a delayed developmental time course relative to other image-forming RGCs. Specifically, ipRGC neurogenesis extends beyond that of other RGCs, and ipRGCs begin innervating the SCN at postnatal ages, unlike most RGCs, which innervate their image-forming targets embryonically. Moreover, the appearance of ipRGC axons in the OPN coincides precisely with the onset of the pupillary light response. Conclusions: Some ipRGCs differ not only functionally but also developmentally from RGCs that mediate pattern-forming vision.

Non‐technical summary In the developing visual system, spontaneous retinal activity plays an important role in the refinement of retinal ganglion cell projections to the dorsal lateral geniculate nucleus (dLGN) of thalamus. How such changes are implemented remains unknown. Recordings of post‐synaptic dLGN cell activity suggest that plateau‐like, L‐type Ca²⁺ channel‐mediated depolarizations figure prominently in remodelling. Plateaus are developmentally regulated and their incidence is controlled by the changing patterns of excitatory and inhibitory connections onto dLGN cells. At early ages there is a high degree of retinal convergence, and excitatory post‐synaptic events summate to produce depolarizations sufficient to activate plateaus. As these excitatory inputs are pruned and inhibitory connections emerge, the net excitatory drive is reduced and plateaus wane. Additionally, L‐type channels are highly expressed at young ages, and subunit disruptions resulting in decreased expression also affect the incidence of plateaus. These studies help elucidate the mechanisms underlying activity‐dependent refinement of sensory connections.

The dorsal lateral geniculate nucleus (dLGN) of the mouse has emerged as a model system in the study of thalamic circuit development. However, there is still a lack of information regarding how and when various types of retinal and nonretinal synapses develop. We examined the synaptic organization of the developing mouse dLGN in the common pigmented C57/BL6 strain, by recording the synaptic responses evoked by electrical stimulation of optic tract axons, and by investigating the ultrastructure of identified synapses. At early postnatal ages (P14), when optic tract stimulation routinely evoked an excitatory postsynaptic potential/inhibitory postsynaptic potential (EPSP/IPSP) sequence, with the latter having both a GABA_A and GABA_B component. Electrophysiological and ultrastructural observations were consistent. At P7, many synapses were present, but synaptic profiles lacked the ultrastructural features characteristic of the adult dLGN, and little γ‐aminobutyric acid (GABA) could be detected by using immunocytochemical techniques. In contrast, by P14, GABA staining was robust, mature synaptic profiles of retinal and nonretinal origin were easily distinguished, and the size and proportion of synaptic contacts were similar to those of the adult. The emergence of nonretinal synapses coincides with pruning of retinogeniculate connections, and the transition of retinal activity from spontaneous to visually driven. These results indicate that the synaptic architecture of the mouse dLGN is similar to that of other higher mammals, and thus provides further support for its use as a model system for visual system development. J. Comp. Neurol. 518:622–635, 2010.

The purpose of the present study was to determine whether retinal activity can support long-term changes in synaptic strength in the developing dorsal lateral geniculate nucleus (LGN) of thalamus. To test for this we made use of a rodent in vitro explant preparation in which retinal afferents and the intrinsic circuitry of the LGN remain intact. We repetitively stimulated the optic tract with a tetanus protocol that approximated the temporal features of spontaneous retinal waves. We found the amplitude of extracellular field potentials evoked by retinal stimulation changed significantly after tetanus and that the polarity of these alterations was related to postnatal age. At a time when substantial pruning of retinal connections occurs (postnatal day 1 [P1] to P14), high-frequency stimulation led to an immediate and long-term depression (LTD). However, at times when pruning wanes and adultlike patterns of connectivity are stabilizing (P16 to P30), the identical form of stimulation produced a modest form of potentiation (long-term potentiation [LTP]). The LTD was unaffected by the bath application of γ-aminobutyric acid type A and N-methyl-d-aspartate receptor antagonists. However, both LTD and LTP were blocked by L-type Ca²⁺-channel antagonists. Thus the Ca²⁺ influx associated with L-type channel activation mediates the induction of synaptic plasticity and may signal the pruning and subsequent stabilization of developing retinogeniculate connections.

Much of our present understanding about the mechanisms contributing to the activity-dependent refinement of sensory connections comes from experiments done in the retinogeniculate pathway. In recent years the mouse has emerged as a model system of study. This review outlines the major changes in connectivity that occur in this species and a potential mechanism that can account for such remodelling. During early postnatal life when spontaneous activity of retinal ganglion cells sweeps across the retina in waves, retinal projections from the two eyes to the dorsal lateral geniculate nucleus (LGN) segregate to form non-overlapping eye-specific domains. There is a loss of binocular innervation, a pruning of excitatory inputs from a dozen or more to one or two, and the emergence of inhibitory circuitry. Many of these changes underlie the development of precise eye-specific visual maps and receptive field structure of LGN neurons. Retinal activity plays a major role both in the induction and maintenance of this refinement. The activity-dependent influx of Ca(2+) through L-type channels and associated activation of CREB signalling may underlie the pruning and stabilization of developing retinogeniculate connections.