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Activity- induced MeCP2 phosphorylation regulates
retinogeniculate synapse refinement

Christopher P. Tzenga, Tess Whitwam, Lisa D. Boxer, Emmy Li, Andrew Silberfeld, Sara Trowbridge, Kevin Mei, Cindy Lin, Rebecca Shamah, Eric C. Griffith, William Renthal, Chinfei Chen, and Michael E. Greenberg

PNAS, Vol. 120, No. 44, 2023

Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MECP2 causes miswiring of neural circuits due to defects in the brain’s capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the mouse brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines...

Brainstem serotonin neurons selectively gate retinal information flow to thalamus

Retinal ganglion cell (RGC) types relay parallel streams of visual feature information. We hypothesized that neuromodulators might efficiently control which visual information streams reach the cortex by selectively gating transmission from specific RGC axons in the thalamus. Using fiber photometry recordings, we found that optogenetic stimulation of serotonergic axons in primary visual thalamus of awake mice suppressed ongoing and visually evoked calcium activity and glutamate release from RGC boutons...

Functional convergence of on-off direction-selective ganglion cells in the visual thalamus

Qiufen JiangElizabeth Y LitvinaHéctor Acarón LedesmaGuanhua ShuTakuma Sonoda, Wei Wei, and Chinfei Chen

Current Biology, Vol. 32, Issue 14, pp. 3110-3120, 2022

In the mouse visual system, multiple types of retinal ganglion cells (RGCs) each encode distinct features of the visual space. A clear understanding of how this information is parsed in their downstream target, the dorsal lateral geniculate nucleus (dLGN), remains elusive. Here, we characterized retinogeniculate connectivity in Cart-IRES2-Cre-D and BD-CreER2 mice, which labels subsets of on-off direction-selective ganglion cells (ooDSGCs) tuned to the vertical directions and to only ventral motion, respectively...

Organization, Function, and Development of the Mouse Retinogeniculate Synapse

Liang Liang and Chinfei Chen

Annual Review of Vision Science, Vol. 6, pp. 261-285, 2020

Visual information is encoded in distinct retinal ganglion cell (RGC) types in the eye tuned to specific features of the visual space. These streams of information project to the visual thalamus, the first station of the image-forming pathway. In the mouse, this connection between RGCs and thalamocortical neurons, the retinogeniculate synapse, has become a powerful experimental model for understanding how circuits in the thalamus are constructed to process these incoming lines of information...

Retinal Inputs to the Thalamus Are Selectively Gated by Arousal

The brain can flexibly filter out sensory information in a manner that depends on behavioral state. In the visual thalamus and cortex, arousal and locomotion are associated with changes in the magnitude of responses to visual stimuli. Here, we asked whether such modulation of visual responses might already occur at an earlier stage in this visual pathway. We measured neural activity of retinal axons using wide-field and two-photon calcium imaging in awake mouse thalamus across arousal states associated with different pupil sizes. Surprisingly, visual responses to drifting gratings in retinal axonal boutons were robustly modulated by arousal level in a manner that varied across stimulus dimensions and across functionally distinct subsets of boutons...

Circuitry Underlying Experience-Dependent Plasticity in the Mouse Visual System

Bryan M Hooks and Chinfei Chen

Neuron, Vol. 6, pp. 261-285, 2020

Since the discovery of ocular dominance plasticity, neuroscientists have understood that changes in visual experience during a discrete developmental time, the critical period, trigger robust changes in the visual cortex. State-of-the-art tools used to probe connectivity with cell-type-specific resolution have expanded the understanding of circuit changes underlying experience-dependent plasticity. Here, we review the visual circuitry of the mouse, describing projections from retina to thalamus, between thalamus and cortex, and within cortex. We discuss how visual circuit development leads to precise connectivity and identify synaptic loci, which can be altered by activity or experience...

Visual Experience-Dependent Expression of Fn14 Is

Required for Retinogeniculate Refinement

Lucas Cheadle, Christopher P Tzeng, Brian T Kalish, David A Harmin, Samuel Rivera, Emi Ling, M Aurel Nagy, Sinisa Hrvatin, Linda Hu, Hume Stroud, Linda C Burkly, Chinfei Chen, and Michael E Greenberg

Neuron, 8 August 2018, Volume 99

Sensory experience influences the establishment of neural connectivity through molecular mechanisms that remain unclear. Here, we employ single-nucleus RNA sequencing to investigate the contribution of sensory-driven gene expression to synaptic refinement in the dorsal lateral geniculate nucleus of the thalamus, a region of the brain that processes visual information. We find that visual experience induces the expression of the cytokine receptor Fn14 in excitatory thalamocortical neurons...

Heterogeneity of retinogeniculate axon arbors

Y. Kate Hong, Eliza F. Burr, Joshua R. Sanes, and Chinfei Chen

European Journal of Neuroscience, Vol. 49, pp. 948–956, 2018

The retinogeniculate synapse transmits information from retinal ganglion cells (RGC) in the eye to thalamocortical relay neurons in the visual thalamus, the dorsal lateral geniculate nucleus (dLGN). Studies in mice have identified genetic markers for distinct classes of RGCs encoding different features of the visual space, facilitating the dissection of RGC subtype-specific physiology and anatomy. In this study, we examine the morphological properties of axon arbors of the BD-RGC class of ON-OFF direction selective cells that, by definition, exhibit a stereotypic dendritic arbor and termination pattern in the retina...

A Fine Scale Functional Logic to Convergence from Retina to Thalamus

Liang Liang, Alex Fratzl, Glenn Goldley, Rohan N. Ramesh, Arthur U. Sugden, Josh L. Morgan, Chinfei Chen, Mark L. Andermann

Cell, 31 May 2018, Volume 173, Issue 6

Numerous well-defined classes of retinal ganglion cells innervate the thalamus to guide image-forming vision, yet the rules governing their convergence and divergence remain unknown. Using two-photon calcium imaging in awake mouse thalamus, we observed a functional arrangement of retinal ganglion cell axonal boutons in which coarse-scale retinotopic ordering gives way to fine-scale organization based on shared preferences for other visual features...

Functional Convergence at the Retinogeniculate Synapse

Elizabeth Y. Litvina and Chinfei Chen
Neuron 96, 11 October 2017, Volume 4, Issue 1

Precise connectivity between retinal ganglion cells (RGCs) and thalamocortical (TC) relay neurons is thought to be essential for the transmission of visual information. Consistent with this view, electrophysiological measurements have previously estimated that 1–3 RGCs converge onto a mouse geniculate TC neuron. Recent advances in connectomics and rabies tracing have yielded much higher estimates of retinogeniculate convergence, although not all identified contacts may be functional. Here we use optogenetics and a computational simulation to determine the number of functionally relevant retinogeniculate inputs onto TC neurons in mice...

An evolving view of retinogeniculate transmission

Elizabeth Y Litvina and Chinfei Chen
Visual Neuroscience, 29 August 2017, Volume 34

The thalamocortical (TC) relay neuron of the dorsoLateral Geniculate Nucleus (dLGN) has borne its imprecise label for many decades in spite of strong evidence that its role in visual processing transcends the implied simplicity of the term “relay”. The retinogeniculate synapse is the site of communication between a retinal ganglion cell and a TC neuron of the dLGN. Activation of retinal fibers in the optic tract causes reliable, rapid, and robust postsynaptic potentials that drive postsynaptics spikes in a TC neuron...

The Importance of Constructive Feedback: Implications of Top Down Regulation in the Development of Neural Circuits

Andrew D. Thompson and Chinfei Chen
Neurogenesis, 3 March 2017, Volume 4, Issue 1

Neural circuits in sensory pathways develop through a general strategy of overproduction of synapses followed by activity-driven pruning to fine-tune connectivity for optimal function. The early visual pathway, consisting of the retina!visual thalamus!primary visual cortex, has served for decades as a powerful model system for probing the mechanisms and logic of this process. In addition to these feedforward projections, the early visual pathway also includes a substantial feedback component in the form of corticothalamic projections from the deepest layer of primary visual cortex...

Cortical Feedback Regulates Feedforward Retinogeniculate Refinement

Andrew D. Thompson, Nathalie Picard, Lia Min, Michela Fagiolini, Chinfei Chen
Neuron, 7 September 2016, Volume 91, Issue 5, 1021-1033

According to the prevailing view of neural development, sensory pathways develop sequentially in a feedforward manner, whereby each local microcircuit refines and stabilizes before directing the wiring of its downstream target. In the visual system, retinal circuits are thought to mature first and direct refinement in the thalamus, after which cortical circuits refine with experience-dependent plasticity. In contrast, we now show that feedback from cortex to thalamus critically regulates refinement of the retinogeniculate projection during a discrete window in development, beginning at postnatal day 20 in mice...

Untangling the Web between Eye and Brain

Chen C, Bickford ME, Hirsch JA
Cell, 24 March 2016, Volume 165, Issue 1, 20-21

How is the picture of the visual scene that the eye encodes represented by neural circuits in the brain? In this issue of Cell, Morgan et al. address this question by forming an ultrastructural “connectome” of the mouse’s visual thalamus that depicts individual retinal afferents and every contact these form with target relay cells.

Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

Bei F, Lee HH, Liu X, Gunner G, Jin H, Ma L, Wang C, Hou L, Hensch TK, Frank E, Sanes JR, Chen C, Fagiolini M, He Z.
Cell, 14 January 2016, Volume 164, Issue 1-2, 219-32

Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function...

Refinement of the Retinogeniculate Synapse by Bouton Clustering

Y. Kate Hong, SuHong Park, Elizabeth Y. Litvina, Jose Morales, Joshua R. Sanes, Chinfei Chen
Neuron, 22 October 2014, Volume 84, Issue 2, 332–339

Mammalian sensory circuits become refined over development in an activity-dependent manner. Retinal ganglion cell (RGC) axons from each eye first map to their target in the geniculate and then segregate into eye-specific layers by the removal and addition of axon branches. Once segregation is complete, robust functional remodeling continues as the number of afferent inputs to each geniculate neuron decreases from many to a few. It is widely assumed that large-scale axon retraction underlies this later phase of circuit refinement. On the contrary, RGC axons remain stable during functional pruning...

Changes in input strength and number are driven by distinct mechanisms at the retinogeniculate synapse

David J. Lin, Erin Kang, Chinfei Chen
Journal of Neurophysiology, August 2014, Volume 112, Issue 4, 942-950

Recent studies have demonstrated that vision influences the functional remodeling of the mouse retinogeniculate synapse, the connection between retinal ganglion cells and thalamic relay neurons in the dorsal lateral geniculate nucleus (LGN). Initially, each relay neuron receives a large number of weak retinal inputs. Over a 2- to 3-wk developmental window, the majority of these inputs are eliminated, and the remaining inputs are strengthened. This period of refinement is followed by a critical period when visual experience changes the strength and connectivity of the retinogeniculate synapse. Visual deprivation of mice by dark rearing from postnatal day (P)20 results in a dramatic weakening of synaptic strength and recruitment of additional inputs...

A Role for Stargazin in Experience-Dependent Plasticity

Susana R. Louros, Bryan M. Hooks, Liza Litvina, Ana Luisa Carvalho, Chinfei Chen
Cell Reports, 12 June 2014, Volume 7, Issue 5, 1614-1625

During development neurons are constantly refining their connections in response to changes in activity. Experience-dependent plasticity is a key form of synaptic plasticity, involving changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) accumulation at synapses. Here we report a critical role for the AMPAR auxiliary subunit, stargazin, in this plasticity. We show that stargazin is functional at the retinogeniculate synapse and that in the absence of stargazin, the refinement of the retinogeniculate synapse is specifically disrupted during the experience-dependent phase...

Prolonged synaptic currents increase relay neuron firing at the developing retinogeniculate synapse

Jessica L. Hauser, Xiaojin Liu, Elizabeth Y. Litvina, and

Chinfei Chen
Journal of Neurophysiology, 25 June 2014,  Issue 112, 1714-1728

The retinogeniculate synapse, the connection between retinal ganglion cells (RGC) and thalamic relay neurons, undergoes robust changes in connectivity over development. This process of synapse elimination and strengthening of remaining inputs is thought to require synapse specificity. Here we show that glutamate spillover and asynchronous release are prominent features of retinogeniculate synaptic transmission during this period. The immature excitatory postsynaptic currents exhibit a slow decay time course that is sensitive to low-affinity glutamate receptor antagonists and extracellular calcium concentrations, consistent with glutamate spillover. Furthermore, we uncover and characterize a novel, purely spillover-mediated AMPA receptor current from immature relay neurons...

Visual acuity development and plasticity in the absence of sensory experience

Kang E, Durand S, LeBlanc JJ, Hensch TK, Chen C, Fagiolini M
Journal of Neuroscience,6 November 2013, Volume 33, Issue 45, 17789-17796

Visual circuits mature and are refined by sensory experience. However, significant gaps remain in our understanding how deprivation influences the development of visual acuity in mice. Here, we perform a longitudinal study assessing the effects of chronic deprivation on the development of the mouse subcortical and cortical visual circuits using a combination of behavioral optomotor testing, in vivo visual evoked responses (VEP) and single-unit cortical recordings. As previously reported, orientation tuning was degraded and onset of ocular dominance plasticity was delayed and remained open in chronically deprived mice....

Metabotropic glutamate receptors and glutamate transporters shape transmission at the developing retinogeniculate synapse

Hauser JL, Edson EB, Hooks BM, Chen C
Journal of Neurophysiology, 17 Oct. 2012, Issue 109, pages 113-123

Over the first few postnatal weeks, extensive remodeling occurs at the developing murine retinogeniculate synapse, the connection between retinal ganglion cells (RGCs) and the visual thalamus. Although numerous studies have described the role of activity in the refinement of this connection, little is known about the mechanisms that regulate glutamate concentration at and around the synapse over development. Here we show that interactions between glutamate transporters and metabotropic glutamate receptors (mGluRs) dynamically control the peak and time course of the excitatory postsynaptic current (EPSC) at the immature synapse. Inhibiting glutamate transporters by bath application of TBOA (DL-threo--benzyloxyaspartic acid) prolonged the decay kinetics...

Wiring and rewiring of the retinogeniculate synapse

Hong YK, Chen C
Current Opinion in Neurobiology, 21 April 2011, Volume 21, Issue 2, 228-37

The formation and refinement of synaptic circuits are areas of research that have fascinated neurobiologists for decades. A recurrent theme seen at many CNS synapses is that neuronal connections are at first imprecise, but refine and can be rearranged with time or with experience. Today, with the advent of new technologies to map and monitor neuronal circuits, it is worthwhile to revisit a powerful experimental model for examining the development and plasticity of synaptic circuits-the retinogeniculate synapse...

Experience-Dependent Retinogeniculate Synapse Remodeling Is Abnormal in MeCP2-Deficient Mice

Joao Noutel, Y. Kate Hong, Byunghee Leu, Erin Kang, Chinfei Chen
Neuron, 14 April 2011, Volume 70, Issue 1, 35-42

Mutations in MECP2 underlie the neurodevelopmental disorder Rett (RTT) syndrome. One hallmark of RTT is relatively normal development followed by a later onset of symptoms. Growing evidence suggests an etiology of disrupted synaptic function, yet it is unclear how these abnormalities explain the clinical presentation of RTT. Here we investigate synapse maturation in Mecp2-deficient mice at a circuit with distinct developmental phases– the retinogeniculate synapse. We find that synapse development in mutants is comparable to that of WT littermates between postnatal days 9–21, indicating that initial phases of synapse formation...

Vision Triggers an Experience-Dependent Sensitive Period at the Retinogeniculate Synapse

Bryan M. Hooks and Chinfei Chen
The Journal of Neuroscience, 30 April 2008, Volume 28, Issue 18, 4807-4817

In the mammalian visual system, sensory experience is widely thought to sculpt cortical circuits during a precise critical period. In contrast, subcortical regions, such as the thalamus, were thought to develop at earlier ages in a vision-independent manner. Recent studies at the retinogeniculate synapse, however, have demonstrated an influence of vision on the formation of synaptic circuits in the thalamus. In mice, dark rearing from birth does not alter normal developmental maturation of the connection between retina and thalamus. However, deprivation 20 d after birth [postnatal day 20 (p20)] resulted in dramatic weakening...

Critical Periods in the Visual System: Changing Views for a Model of Experience-Dependent Plasticity

Bryan M. Hooks, Chinfei Chen
Neuron, 25 October 2007, Volume 56, Issue 2, 312-326

Visual system circuitry, a canonical model system for the study of experience-dependent development, matures before and following the onset of vision. Sensory experience or deprivation during an early critical period results in substantial plasticity and is a crucial factor in establishing the mature circuitry. In adulthood, plasticity has been thought to be reduced or absent. However, recent studies point to the potential for change in neuronal circuits within the mature brain...

Distinct Roles for Spontaneous and Visual Activity in Remodeling of the Retinogeniculate Synapse

Bryan M. Hooks, Chinfei Chen
Neuron,19 October 2006, Volume 52, Issue 2, 281-291

Sensory experience and spontaneous activity play important roles in development of sensory circuits; however, their relative contributions are unclear. Here, we test the role of different forms of activity on remodeling of the mouse retinogeniculate synapse. We found that the bulk of maturation occurs without patterned sensory activity over 4 days spanning eye opening. During this early developmental period, blockade of spontaneous retinal activity by tetrodotoxin, but not visual deprivation, retarded synaptic strengthening and inhibited pruning of excess retinal afferents...

Frequency-Dependent Modulation of Retinogeniculate Transmission by Serotonin

Daniel P. Seeburg, Xiaojin Liu, Chinfei Chen
The Journal of Neuroscience, 1 December 2004, Volume 24, Issue 48, 10950-10962

The relay of visual information converging in the lateral geniculate nucleus (LGN) en route to the visual cortex is modulated by projections from brainstem nuclei. The release of serotonin, one mediator of these effects, has been shown to act at a presynaptic site to inhibit neurotransmitter release at the retinogeniculate synapse, the connection between retinal ganglion cells and thalamocortical relay neurons in the LGN. To understand how serotonergic inhibition of synaptic transmission influences the transfer of information at this synapse, we examined the EPSCs and firing responses of relay neurons...

Presynaptic Modulation of the Retinogeniculate Synapse

Chinfei Chen, Wade G. Regehr
The Journal of Neuroscience, 15 April 2003, Volume 23, Issue 8, 3130-3135

Modulatory projections from brainstem nuclei and intrinsic thalamic interneurons play a significant role in modifying sensory information as it is relayed from the thalamus to the cortex. In the lateral geniculate nucleus (LGN), neurotransmitters released from these modulatory inputs can affect the intrinsic conductances of thalamocortical relay neurons, thus altering their firing properties. Here, we show that in addition to postsynaptic effects, neuromodulators...

Contributions of Receptor Desensitization and Saturation to Plasticity at the Retinogeniculate Synapse

Chinfei Chen, Dawn M. Blitz, Wade G. Regehr
Neuron, 28 February 2002, Volume 33, Issue 5, 779-788

The retinogeniculate synapse conveys visual information from the retina to thalamic relay neurons. Here, we examine the mechanisms of short-term plasticity that can influence transmission at this connection in mouse brain slices. Our studies show that synaptic strength is modified by physiological activity patterns due to marked depression at high frequencies. Postsynaptic mechanisms of plasticity make prominent contributions to this synaptic depression...

Developmental Remodeling of the Retinogeniculate Synapse

Chinfei Chen, Wade G. Regehr
Neuron, December 2000, Volume 28, Issue 3, 955-966

Anatomical rearrangement of retinogeniculate connections contributes to the refinement of synaptic circuits in the developing visual system, but the underlying changes in synaptic function are unclear. Here, we study such changes in mouse brain slices. Each geniculate cell receives a surprisingly large number of retinal inputs (>20) well after eye-specific zones are formed. All but one to three of these inputs are eliminated over a 3-week period spanning eye opening...

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