Catherine A. Leamey

Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision.

Binocular vision requires an exquisite matching of projections from each eye to form a cohesive representation of the visual world. Eye-specific inputs are anatomically segregated, but in register in the visual thalamus, and overlap within the binocular region of primary visual cortex. Here, we show that the transmembrane protein Ten_m3 regulates the alignment of ipsilateral and contralateral projections. It is expressed in a gradient in the developing visual pathway, which is consistently highest in regions that represent dorsal visual field. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral, but not contralateral, projections, and exhibit pronounced deficits when performing visually mediated behavioural tasks. It is likely that the functional deficits arise from the interocular mismatch, because they are reversed by acute monocular inactivation. We conclude that Ten_m3 plays a key regulatory role in the development of aligned binocular maps, which are required for normal vision.

Gene expression patterns in visual cortex during the critical period: Synaptic stabilization and reversal by visual deprivation

The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene, synCAM, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.

Teneurins: important regulators of neural circuitry.

Teneurin (Ten-m/Odz) molecules represent a highly conserved family of four type II transmembrane proteins in vertebrates (Ten-m1-4), which exist as homodimers and undergo homophilic interactions. Each is expressed in distinct, and often interconnected, areas of the developing nervous system. Different Ten-ms have complementary expression patterns. In vitro and in vivo studies support roles for teneurins in promoting neurite outgrowth and cell adhesion. Furthermore, the intracellular domains of at least two teneurins can undergo proteolytic cleavage and translocate to the nucleus where they regulate transcriptional activity. Recent in vivo studies show that teneurins play important roles in regulating connectivity in the nervous system. Knockdown in C. elegans resulted in abnormal axon guidance and cell migration, while targeted deletion of Ten-m3 in mice revealed it is required for the guidance of retinal axons and generation of visual topography. It is likely that all teneurins play important roles during neural development.

Nitric oxide as a signaling molecule in visual system development.

The lateral geniculate nucleus (LGN) of the ferret is characterized by the readily discernible anatomical patterning of afferent terminations from the retina into both eye-specific layers and On/Off sublaminae. The eye-specific layers form during the first post-natal week, and On/Off sublaminae become apparent during the third to fourth post-natal weeks. The post-natal appearance of these patterns thus provides an advantageous model for the study of the mechanisms of activity-dependent development. The second phase of pattern formation, the appearance of On/Off sublaminae, involves the elaboration of appropriately placed axonal terminals and the restriction (or retraction) of inappropriately placed terminals. Previous work has demonstrated that this process is dependent on the activation of NMDA-receptors. Other studies have provided strong evidence that nitric oxide, a diffusible gas which is produced downstream of NMDA-receptor activation, acts as a retrograde messenger molecule to induce changes in pre-synaptic structures. In this article we review the evidence that nitric oxide plays a role in activity-dependent synaptic plasticity in the developing retinogeniculate pathway. The role of nitric oxide in other aspects of visual system development is also discussed.

Enrichment from Birth Accelerates the Functional and Cellular Development of a Motor Control Area in the Mouse

Background There is strong evidence that sensory experience in early life has a profound influence on the development of sensory circuits. Very little is known, however, about the role of experience in the early development of striatal networks which regulate both motor and cognitive function. To address this, we have investigated the influence of early environmental enrichment on motor development. Methodology/Principal Findings Mice were raised in standard or enriched housing from birth. For animals assessed as adults, half of the mice had their rearing condition reversed at weaning to enable the examination of the effects of pre- versus post-weaning enrichment. We found that exclusively pre-weaning enrichment significantly improved performance on the Morris water maze compared to non-enriched mice. The effects of early enrichment on the emergence of motor programs were assessed by performing behavioural tests at postnatal day 10. Enriched mice traversed a significantly larger region of the test arena in an open-field test and had improved swimming ability compared to non-enriched cohorts. A potential cellular correlate of these changes was investigated using Wisteria-floribunda agglutinin (WFA) staining to mark chondroitin-sulfate proteoglycans (CSPGs). We found that the previously reported transition of CSPG staining from striosome-associated clouds to matrix-associated perineuronal nets (PNNs) is accelerated in enriched mice. Conclusions/Significance This is the first demonstration that the early emergence of exploratory as well as coordinated movement is sensitive to experience. These behavioural changes are correlated with an acceleration of the emergence of striatal PNNs suggesting that they may consolidate the neural circuits underlying these behaviours. Finally, we confirm that pre-weaning experience can lead to life long changes in the learning ability of mice.

Ten-m2 Is Required for the Generation of Binocular Visual Circuits

Functional binocular vision requires that inputs arising from the two retinae are integrated and precisely organized within central visual areas. Previous studies have demonstrated an important role for one member of the Ten-m/Odz/teneurin family, Ten-m3, in the mapping of ipsilateral retinal projections. Here, we have identified a distinct role for another closely related family member, Ten-m2, in the formation of the ipsilateral projection in the mouse visual system. Ten-m2 expression was observed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) of the developing mouse. Anterograde and retrograde tracing experiments in Ten-m2 knock-out (KO) mice revealed a specific decrease in ipsilateral retinal ganglion cells projecting to dLGN and SC. This reduction was most prominent in regions corresponding to ventral retina. No change in the topography of ipsilateral or contralateral projections was observed. While expression of a critical ipsilateral fate determinant, Zic2, appeared unaltered, a notable reduction in one of its downstream targets, EphB1, was observed in ventral retina, suggesting that Ten-m2 may interact with this molecular pathway. Immunohistochemistry for c-fos, a neural activity marker, revealed that the area of V1 driven by ipsilateral inputs was reduced in KOs, while the ratio of ipsilateral-to-contralateral responses contributing to binocular activation during visually evoked potential recordings was also diminished. Finally, a novel two-alternative swim task revealed specific deficits associated with dorsal visual field. These data demonstrate a requirement for Ten-m2 in the establishment of ipsilateral projections, and thus the generation of binocular circuits, critical for mammalian visual function.

Ten-m3 is required for the development of topography in the ipsilateral retinocollicular pathway.

Background The alignment of ipsilaterally and contralaterally projecting retinal axons that view the same part of visual space is fundamental to binocular vision. While much progress has been made regarding the mechanisms which regulate contralateral topography, very little is known of the mechanisms which regulate the mapping of ipsilateral axons such that they align with their contralateral counterparts. Results Using the advantageous model provided by the mouse retinocollicular pathway, we have performed anterograde tracing experiments which demonstrate that ipsilateral retinal axons begin to form terminal zones (TZs) in the superior colliculus (SC), within the first few postnatal days. These appear mature by postnatal day 11. Importantly, TZs formed by ipsilaterally-projecting retinal axons are spatially offset from those of contralaterally-projecting axons arising from the same retinotopic location from the outset. This pattern is consistent with that required for adult visuotopy. We further demonstrate that a member of the Ten-m/Odz/Teneurin family of homophilic transmembrane glycoproteins, Ten-m3, is an essential regulator of ipsilateral retinocollicular topography. Ten-m3 mRNA is expressed in a high-medial to low-lateral gradient in the developing SC. This corresponds topographically with its high-ventral to low-dorsal retinal gradient. In Ten-m3 knockout mice, contralateral ventrotemporal axons appropriately target rostromedial SC, whereas ipsilateral axons exhibit dramatic targeting errors along both the mediolateral and rostrocaudal axes of the SC, with a caudal shift of the primary TZ, as well as the formation of secondary, caudolaterally displaced TZs. In addition to these dramatic ipsilateral-specific mapping errors, both contralateral and ipsilateral retinocollicular TZs exhibit more subtle changes in morphology. Conclusions We conclude that important aspects of adult visuotopy are established via the differential sensitivity of ipsilateral and contralateral axons to intrinsic guidance cues. Further, we show that Ten-m3 plays a critical role in this process and is particularly important for the mapping of the ipsilateral retinocollicular pathway.

Intrinsic patterning and experience-dependent mechanisms that generate eye-specific projections and binocular circuits in the visual pathway

A defining feature of the mammalian nervous system is its complex yet precise circuitry. The mechanisms which underlie the generation of neural connectivity are the topic of intense study in developmental neuroscience. The mammalian visual pathway demonstrates precise retinotopic organization in subcortical and cortical pathways, together with the alignment and matching of eye-specific projections, and sophisticated cortical circuitry that enables the extraction of features underlying vision. New approaches employing molecular-genetic analyses, transgenic mice, novel recombinant probes, and high-resolution imaging are contributing to rapid progress and a new synthesis in the field. These approaches are revealing the ways in which intrinsic patterning mechanisms act in concert with experience-dependent mechanisms to shape visual projections and circuits.

Deletion of Ten-m3 Induces the Formation of Eye Dominance Domains in Mouse Visual Cortex

The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex.

Perineuronal nets play a role in regulating striatal function in the mouse.

The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.