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Marla B Feller

Publications and source records attributed to Marla B Feller.

17 recordsLinked to original sources
PubMed2006

Imaging of cAMP levels and protein kinase A activity reveals that retinal waves drive oscillations in second-messenger cascades.

Recent evidence demonstrates that low-frequency oscillations of intracellular calcium on timescales of seconds to minutes drive distinct aspects of neuronal development, but the mechanisms by which these calcium transients are coupled to signaling cascades are not well understood. Here we test the hypothesis that spontaneous electrical activity activates protein kinase A (PKA). We use live-cell indicators to observe spontaneous and evoked changes in cAMP levels and PKA activity in developing retinal neurons. Expression of cAMP and PKA indicators in neonatal rat retinal explants reveals spontaneous oscillations in PKA activity that are temporally correlated with spontaneous depolarizations associated with retinal waves. In response to short applications of forskolin, dopamine, or high-potassium concentration, we image an increase in cAMP levels and PKA activity, indicating that this second-messenger pathway can be activated quickly by neural activity. Depolarization-evoked increases in PKA activity were blocked by the removal of extracellular calcium, indicating that they are mediated by a calcium-dependent mechanism. These findings demonstrate for the first time that spontaneous activity in developing circuits is correlated with activation of the cAMP/PKA pathway and that PKA activity is turned on and off on the timescale of tens of seconds. These results show a link between neural activity and an intracellular biochemical cascade associated with plasticity, axon guidance, and neural differentiation.

Animals↗
PubMed2006

Early retinal activity and visual circuit development.

Does spontaneous retinal activity prior to vision play a role in the establishment of visual maps? In this issue of Neuron, two separate papers by Huberman et al. and Hooks and Chen demonstrate a role for early spontaneous retinal activity in the establishment of ocular dominance columns and synaptic refinement at retinogeniculate synapses.

Action Potentials↗
PubMed2005

Expression and function of the neuronal gap junction protein connexin 36 in developing mammalian retina.

With the advent of transgenic mice, much has been learned about the expression and function of gap junctions. Previously, we reported that retinal ganglion cells in mice lacking the neuronal gap junction protein connexin 36 (Cx36) have nearly normal firing patterns at postnatal day 4 (P4) but many more asynchronous action potentials than wild-type mice at P10 (Torborg et al. [2005] Nat. Neurosci. 8:72-78). With the goal of understanding the origin of this increased activity in Cx36-/- mice, we used a transgenic mouse (Deans et al. [2001] Neuron 31:477-485) to characterize the developmental expression of a Cx36 reporter in the retina. We found that Cx36 was first detected weakly at P2 and gradually increased in expression until it reached an adult pattern at P14. Although the onset of expression varied by cell type, we identified Cx36 in the glycinergic AII amacrine cell, glutamatergic cone bipolar cell, and retinal ganglion cells (RGCs). In addition, we used calcium imaging and multielectrode array recording to characterize further the firing patterns in Cx36-/- mice. Both correlated and asynchronous action potentials in P10 Cx36-/- RGCs were significantly inhibited by bath application of an ionotropic glutamate receptor antagonist, indicating that the increase in activity was synaptically mediated. Hence, both the expression patterns and the physiology suggest an increasing role for Cx36-containing gap junctions in suppressing RGC firing between waves during postnatal retinal development.

Animals↗
PubMed2005

Spontaneous patterned retinal activity and the refinement of retinal projections.

A characteristic feature of sensory circuits is the existence of orderly connections that represent maps of sensory space. A major research focus in developmental neurobiology is to elucidate the relative contributions of neural activity and guidance molecules in sensory map formation. Two model systems for addressing map formation are the retinotopic map formed by retinal projections to the superior colliculus (SC) (or its non-mammalian homolog, the optic tectum (OT)), and the eye-specific map formed by retinal projections to the lateral geniculate nucleus of the thalamus. In mammals, a substantial portion of retinotopic and eye-specific refinement of retinal axons occurs before vision is possible, but at a time when there is a robust, patterned spontaneous retinal activity called retinal waves. Though complete blockade of retinal activity disrupts normal map refinement, attempts at more refined perturbations, such as pharmacological and genetic manipulations that alter features of retinal waves critical for map refinement, remain controversial. Here we review: (1) the mechanisms that underlie the generation of retinal waves; (2) recent experiments that have investigated a role for guidance molecules and retinal activity in map refinement; and (3) experiments that have implicated various signaling cascades, both in retinal ganglion cells (RGCs) and their post-synaptic targets, in map refinement. It is likely that an understanding of retinal activity, guidance molecules, downstream signaling cascades, and the interactions between these biological systems will be critical to elucidating the mechanisms of sensory map formation.

Animals↗
PubMed2005

Retinal waves: mechanisms and function in visual system development.

A characteristic feature of developing neural networks is spontaneous periodic activity. In the developing retina, retinal ganglion cells fire bursts of action potentials that drive large increases in intracellular calcium concentration with a periodicity of minutes. These periodic bursts of action potentials propagate across the developing inner retina as waves, driving neighboring retinal ganglion cells to fire in a correlated fashion. Here we will review recent progress in elucidating the mechanisms in mammals underlying retinal wave propagation and those regulating the periodicity with which these retinal waves occur. In addition, we will review recent experiments indicating that retinal waves are critical for refining retinal projections to their primary targets in the central visual system and may be involved in driving developmental processes within the retina itself.

Animals↗
PubMed2005

A precritical period for plasticity in visual cortex.

One of the seminal discoveries in developmental neuroscience is that altering visual experience through monocular deprivation can alter both the physiological and the anatomical representation of the two eyes, called ocular dominance columns, in primary visual cortex. This rearrangement is restricted to a critical period that starts a few days or weeks after vision is established and ends before adulthood. In contrast to the original hypothesis proposed by Hubel and Wiesel, ocular dominance columns are already substantially formed before the onset of the critical period. Indeed, before the critical period there is a period of ocular dominance column formation during which there is robust spontaneous activity and visual experience. Recent findings raise important questions about whether activity guides ocular dominance column formation in this 'precritical period'. One developmental event that marks the passage from the precritical period to the critical period is the activation of a GABAergic circuit. How these events trigger the transition from the precritical to critical period is not known.

Animals↗
PubMed2004

High frequency, synchronized bursting drives eye-specific segregation of retinogeniculate projections.

Blockade of retinal waves prevents the segregation of retinogeniculate afferents into eye-specific layers in the visual thalamus. However, the key features of retinal waves that drive this refinement are controversial. Some manipulations of retinal waves lead to normal eye-specific segregation but others do not. By comparing retinal spiking patterns in several mutant mice with differing levels of eye-specific segregation, we show that the presence of high-frequency bursts synchronized across neighboring retinal ganglion cells correlates with robust eye-specific segregation and that the presence of high levels of asynchronous spikes does not inhibit this segregation. These findings provide a possible resolution to previously described discrepancies regarding the role of retinal waves in retinogeniculate segregation.

Action Potentials↗
PubMed2004

Unbiased analysis of bulk axonal segregation patterns.

The projection of retinal ganglion cell axons to the dorsal lateral geniculate nucleus of the thalamus (dLGN) is organized into eye-specific layers, which are macroscopic structures that reflect the bulk organization of thousands of axons. The processes that underlie the formation of these layers is the focus of research in several laboratories. The recent advent of fluorescently tagged tracers allows for the simultaneous visualization of axons from both eyes in the same dLGN section and therefore the analysis of axonal segregation patterns. However, the techniques traditionally used to quantify eye-specific segregation are far from standardized. Here we present an analysis method that objectively quantifies the extent of segregation. We apply this analyses to dLGN images from mice with normal retinogeniculate projection patterns and genetically altered mice with dramatically altered projection patterns. In addition, we compare dLGN images acquired at different optical resolutions to measure the spatial scale over which we can determine segregation unambiguously.

Animals↗
PubMed2004

L-type calcium channel agonist induces correlated depolarizations in mice lacking the beta2 subunit nAChRs.

Retinal waves are mediated in part by activation of nicotinic receptors containing the beta2 subunit. Mice deficient in beta2 containing nAChRs have maintained firing of action potentials but do not support correlated waves. As a result, beta2-/- mice have inhibited refinement of circuits within the retina as well as retinal projections to the CNS. Previously, we observed that correlated increases in calcium reminiscent of retinal waves could be induced in beta2-/- retina by pharmacological application of the L-type calcium channel agonist, FPL-64176. Here, we characterize FPL-induced activity patterns in beta2-/- retina using both whole cell and multielectrode array recordings. FPL-induced strong depolarizations in previously non-spiking beta2-/- retinal ganglion cells. Though these strong depolarizations were likely to underlie the FPL-induced calcium transients, they led to highly variable effects on the spiking of individual retinal ganglion cells. In addition, induced spiking activity had significantly weaker nearest-neighbor correlations than WT mice. Initial attempts of intraocular injections of FPL in beta2-/- mice did not rescue eye-specific layer formation. These findings indicate that activity induced by FPL is not sufficient for driving eye-specific segregation in beta2-/- mice.

Animals↗
PubMed2004

Emergence of realistic retinal networks in culture promoted by the superior colliculus.

The developing retina is characterized by 'retinal waves', spontaneous depolarizations that propagate through a developing network of interneurons and retinal ganglion cells. Although the circuitry underlying retinal waves is well characterized, the secreted factors that are critical for its normal development are not defined. Dissociated cell culture provides an ideal system for defining these factors; however, it is difficult to recapitulate retinal circuitry in culture. Here we demonstrate that by culturing dissociated retinal neurons in the presence of cells from the superior colliculus (SC), retinal neurons form networks that are similar to those described in the intact retina. Whole-cell voltage clamp recordings reveal the presence of a spontaneously active network of interneurons. In addition, we observed spontaneous, propagating activity reminiscent of that observed in the intact retina. We propose that the presence of factors secreted from the SC results in the development of networks that reproduce critical features of the intact retina.

Animals↗
PubMed2003

Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development.

During retinocollicular map development, spontaneous waves of action potentials spread across the retina, correlating activity among neighboring retinal ganglion cells (RGCs). To address the role of retinal waves in topographic map development, we examined wave dynamics and retinocollicular projections in mice lacking the beta2 subunit of the nicotinic acetylcholine receptor. beta2(-/-) mice lack waves during the first postnatal week, but RGCs have high levels of uncorrelated firing. By P8, the wild-type retinocollicular projection remodels into a refined map characterized by axons of neighboring RGCs forming focal termination zones (TZs) of overlapping arbors. In contrast, in P8 beta2(-/-) mice, neighboring RGC axons form large TZs characterized by broadly distributed arbors. At P8, glutamatergic retinal waves appear in beta2(-/-) mice, and later, visually patterned activity appears, but the diffuse TZs fail to remodel. Thus, spontaneous retinal waves that correlate RGC activity are required for retinotopic map remodeling during a brief early critical period.

Action Potentials↗
PubMed2003

Visual system plasticity begins in the retina.

Visual experience is known to induce developmental plasticity in visual cortex; now, Tian and Copenhagen report that experience regulates the development of retinal circuitry itself. Both pruning of retinal ganglion dendrites into ON or OFF sublamina and the emergence of pure ON versus OFF responses require visual experience.

Animals↗
PubMed2002

Retinogeniculate axons undergo eye-specific segregation in the absence of eye-specific layers.

Spontaneous retinal activity mediated by cholinergic transmission regulates the segregation of retinal ganglion cell axons in the lateral geniculate nucleus of the thalamus into eye-specific layers. The details of how the layers form are unknown. Mice lacking the beta2 subunit of the neuronal nicotinic acetylcholine receptor lack ACh-mediated waves and as a result, do not form eye-specific layers at any stage of development. However, during the second postnatal week, beta2-/- mice have glutamate-mediated waves. Here we show that after the first postnatal week, even in the absence of layers, retinothalamic axons segregate into an unlayered, patchy distribution of eye-specific regions. These results indicate that spontaneous neural activity may independently regulate eye-specific segregation and the formation of layers at the developing retinothalamic projection.

Animals↗
PubMed2002

The role of nAChR-mediated spontaneous retinal activity in visual system development.

In the developing vertebrate retina, nAChR synapses are among the first to appear. This early cholinergic circuitry plays a key role in generating "retinal waves," spontaneously generated waves of action potentials that sweep across the ganglion cell layer. These retinal waves exist for a short period of time during development when several circuits within the visual system are being established. Here I review the cholinergic circuitry of the developing retina and the role these early circuits play in the development of the retina itself and of retinal projections to the lateral geniculate nucleus of the thalamus.

Action Potentials↗
PubMed2002

Dissociated retinal neurons form periodically active synaptic circuits.

Throughout the developing nervous system, immature circuits generate rhythmic activity patterns that influence the formation of adult networks. The cellular mechanisms underlying this spontaneous, correlated activity can be studied in dissociated neuronal cultures. Using calcium imaging and whole cell recording, we showed that cultured dissociated mammalian retinal neurons form networks that produce spontaneous, correlated, highly periodic activity. As the culture matures, the spatial correlations of the periodic calcium transients evolve from being highly synchronized across neighboring cells to propagating across the culture in a wavelike manner reminiscent of retinal waves recorded in vivo. Spontaneous calcium transients and synaptic currents were blocked either by cadmium, tetrodotoxin, or the glutamate receptor antagonist 6,7-dinitroquinoxaline, indicating that the periodic activity was driven primarily by synaptic transmission between retinal ganglion cells. Evoked responses between pairs of ganglion cells exhibited paired-pulse synaptic depression, and the time constant of recovery from this depression was similar to the interval between periodic events. These results suggest that synaptic depression may regulate the frequency of network activity. Together, these findings provide insight into how networks containing primarily excitatory connections generate highly correlated activity.

Amacrine Cells↗
PubMedDate not supplied

Dissociated GABAergic retinal interneurons exhibit spontaneous increases in intracellular calcium.

Early in development, before the retina is responsive to light, neurons exhibit spontaneous activity. Recently it was demonstrated that starburst amacrine cells, a unique class of neurons that secretes both GABA and acetylcholine, spontaneously depolarize. Networks comprised of spontaneously active starburst cells initiate correlated bursts of action potentials that propagate across the developing retina with a periodicity on the order minutes. To determine whether other retinal interneurons have similar "pacemaking" properties, we have utilized cultures of dissociated neurons from the rat retina. In the presence of antagonists for fast neurotransmitter receptors, distinct populations of neurons exhibited spontaneous, uncorrelated increases in intracellular calcium concentration. These increases in intracellular calcium concentration were sensitive to tetrodotoxin, indicating they are mediated by spontaneous membrane depolarizations. By combining immunofluorescence and calcium imaging, we found that 44% of spontaneously active neurons were GABAergic and included starburst amacrine cells. Whole cell voltage clamp recordings in the absence of antagonists for fast neurotransmitters revealed that after 7 days in culture, individual retinal neurons receive bursts of GABA-A receptor mediated synaptic input with a periodicity similar to that measured in spontaneously active GABAergic neurons. Low concentrations of GABA-A receptor antagonists did not alter the inter-burst interval despite significant reduction of post-synaptic current amplitude, indicating that pacemaker activity of GABAergic neurons was not influenced by network interactions. Together, these findings indicate that spiking GABAergic interneurons can function as pacemakers in the developing retina.

2-Amino-5-phosphonovalerate↗