Non-centered spike-triggered covariance analysis reveals neurotrophin-3 as a developmental regulator of receptive field properties of ON-OFF retinal ganglion cells

The functional separation of ON and OFF pathways, one of the fundamental features of the visual system, starts in the retina. During postnatal development, some retinal ganglion cells (RGCs) whose dendrites arborize in both ON and OFF sublaminae of the inner plexiform layer transform into RGCs with dendrites that monostratify in either the ON or OFF sublamina, acquiring final dendritic morphology in a subtype-dependent manner. Little is known about how the receptive field (RF) properties of ON, OFF, and ON-OFF RGCs mature during this time because of the lack of a reliable and efficient method to classify RGCs into these subtypes. To address this deficiency, we developed an innovative variant of Spike Triggered Covariance (STC) analysis, which we term Spike Triggered Covariance - Non-Centered (STC-NC) analysis. Using a multi-electrode array (MEA), we recorded the responses of a large population of mouse RGCs to a Gaussian white noise stimulus. As expected, the Spike-Triggered Average (STA) fails to identify responses driven by symmetric static nonlinearities such as those that underlie ON-OFF center RGC behavior. The STC-NC technique, in contrast, provides an efficient means to identify ON-OFF responses and quantify their RF center sizes accurately. Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller. Importantly, we demonstrate for the first time that neurotrophin-3 (NT-3) regulates the development of physiological properties of ON-OFF center RGCs. Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells. In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.     

Response dynamics of bullfrog ON-OFF RGCs to different stimulus durations

Stimulus duration is an important feature of visual stimulation. In the present study, response properties of bullfrog ON-OFF retinal ganglion cells (RGCs) in exposure to different visual stimulus durations were studied. By using a multi-electrode recording system, spike discharges from ON-OFF RGCs were simultaneously recorded, and the cells’ ON and OFF responses were analyzed. It was found that the ON response characteristics, including response latency, spike count, as well as correlated activity and relative latency between pair-wise cells, were modulated by different light OFF intervals, while the OFF response characteristics were modulated by different light ON durations. Stimulus information carried by the ON and OFF responses was then analyzed, and it was found that information about different light ON durations was more carried by transient OFF response, whereas information about different light OFF intervals were more carried by transient ON response. Meanwhile, more than 80 % information about stimulus durations was carried by firing rate. These results suggest that ON-OFF RGCs are sensitive to different stimulus durations, and they can efficiently encode the information about visual stimulus duration by firing rate.     

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.     

Cell-type specific dendritic contacts between retinal ganglion cells during development.

The extent of a neuron's dendritic field defines the region within which information is processed. The dendritic fields of functionally distinct ON and OFF center retinal ganglion cells (RGCs) form separate mosaics across the retina. Within each mosaic, neighboring dendritic fields overlap by a constant amount, sampling the visual field with the appropriate coverage. Contact-mediated lateral inhibition between neighboring RGCs has long been thought to regulate both the extent and overlap of dendritic fields during development. Here we show that dendro-dendritic contact exists between developing RGCs and occurs in a manner that would regulate the formation of ON and OFF mosaics separately. Dye-filled neighboring ON and OFF ferret alpha RGCs were reconstructed using multiphoton microscopy. At all neonatal ages examined, we observed dendro-dendritic contacts between RGCs of the same sign (ON/ON; OFF/OFF), but never between cells of opposite signs (ON/OFF). Terminal dendrites of one cell often touched a dendrite of its neighbor as they intersected. In some instances, the distal dendrite of one cell formed a fascicle with the proximal process of its neighbor. Alpha cells did not form contacts with neighboring beta cells of the same sign. Together, these observations suggest that dendro-dendritic contact between RGCs is cell-type specific. Dendritic contacts were observed even before the alpha cell arbors were completely stratified, suggesting that cell-cell recognition may take place early in their development. For each cell type, the relative overlap of dendritic fields was constant with age, despite a two-fold increase in field area. We suggest that dendro-dendritic contacts may be sites of intercellular signaling that could regulate local extension of dendrites to maintain the relative overlap of RGCs within a mosaic during development.     

Diversity of Retinal Ganglion Cells Identified by Transient GFP Transfection in Organotypic Tissue Culture of Adult Marmoset Monkey Retina

The mammalian retina has more diversity of neurons than scientists had once believed in order to establish complicated vision processing. In the monkey retina, morphological diversity of retinal ganglion cells (RGCs) besides dominant midget and parasol cells has been suggested. However, characteristic subtypes of RGCs in other species such as bistratified direction-selective ganglion cells (DSGC) have not yet been identified. Increasing interest has been shown in the common marmoset (Callithrix jacchus) monkey as a “super-model” of neuroscientific research. Here, we established organotypic tissue culture of the adult marmoset monkey retina with particle-mediated gene transfer of GFP to survey the morphological diversity of RGCs. We successfully incubated adult marmoset monkey retinas for 2 to 4 days ex vivo for transient expression of GFP. We morphologically examined 121 RGCs out of more than 3240 GFP-transfected cells in 5 retinas. Among them, we identified monostratified or broadly stratified ganglion cells (midget, parasol, sparse, recursive, thorny, and broad thorny ganglion cells), and bistratified ganglion cells (recursive, large, and small bistratified ganglion cells [blue-ON/yellow-OFF-like]). By this survey, we also found a candidate for bistratified DSGC whose dendrites were well cofasciculated with ChAT-positive starburst dendrites, costratified with ON and OFF ChAT bands, and had honeycomb-shaped dendritic arbors morphologically similar to those in rabbits. Our genetic engineering method provides a new approach to future investigation for morphological and functional diversity of RGCs in the monkey retina.     

Light-induced plasticity of synaptic AMPA receptor composition in retinal ganglion cells

Light-evoked responses of all three major classes of?retinal ganglion cells (RGCs) are mediated by NMDA receptors (NMDARs) and AMPA receptors (AMPARs). Although synaptic activity at RGC synapses is highly dynamic, synaptic plasticity has not been observed in adult RGCs. Here, using patch-clamp recordings in dark-adapted mouse retina, we report a retina-specific form of AMPAR plasticity. Both chemical and light activation of NMDARs caused the selective endocytosis of GluA2-containing, Ca(2+)-impermeable AMPARs on RGCs and replacement with GluA2-lacking, Ca(2+)-permeable AMPARs. The plasticity was expressed in ON but not OFF RGCs and was restricted solely to the ON responses in ON-OFF RGCs. Finally, the plasticity resulted in a shift in the light responsiveness of ON RGCs. Thus, physiologically relevant light stimuli can induce a change in synaptic receptor composition of ON RGCs, providing a mechanism by which the sensitivity of RGC responses may be modified under scotopic conditions.     

Dark rearing alters the normal development of spatiotemporal response properties but not of contrast detection threshold in mouse retinal ganglion cells

The mouse visual system is immature when the eyes open two weeks after birth. As in other mammals, some of the maturation that occurs in the subsequent weeks is known to depend on visual experience. Development of the retina, which as the first stage of vision provides the visual information to the brain, also depends on light‐driven activity for proper development but has been less well studied than visual cortical development. The critical properties for retinal encoding of images include detection of contrast and responsiveness to the broad range of temporal stimulus frequencies present in natural stimuli. Here we show that contrast detection threshold and temporal frequency response characteristics of ON and OFF retinal ganglion cells (RGCs), which are poor at eye opening, subsequently undergo maturation, improving RGC performance. Further, we find that depriving mice of visual experience from before birth by rearing them in the dark causes ON and OFF RGCs to have smaller receptive field centers but does not affect their contrast detection threshold development. The modest developmental increase in temporal frequency responsiveness of RGCs in mice reared on a normal light cycle was inhibited by dark rearing only in ON but not OFF RGCs. Thus, these RGC response characteristics are in many ways unaffected by the experience‐dependent changes to synaptic and spontaneous activity known to occur in the mouse retina in the two weeks after eye opening, but specific differences are apparent in the ON vs. OFF RGC populations. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 692–706, 2014     

The development of intrinsic excitability in mouse retinal ganglion cells

Activity-dependent refinement of synaptic connections occurs throughout the developing nervous system, including the visual system. Retinal ganglion cells (RGCs) overproduce synapses then refine them in an activity-dependent manner that segregates RGC connections into multicellular patterns, such as eye-specific regions and retinotopic maps. Ferrets additionally segregate ON and OFF retinogeniculate pathways in an activity-dependent manner. It was unknown whether differences in ON versus OFF intrinsic and spontaneous activity occur in postnatal mouse. The work reported here measured the intrinsic properties and spontaneous activity of morphologically identified postnatal mouse RGCs, and tested the hypothesis that mouse ON and OFF RGCs develop differences in spontaneous activity. We found developmental changes in resting potential, action potential threshold, depolarization to threshold, action potential width, action potential patterns, and maximal firing rates. These results are consistent with the maturation of the intrinsic properties of RGCs extending through the first three postnatal weeks. However, there were no differences among mouse ON, OFF, and multistratified RGCs in intrinsic excitability, spontaneous synaptic drive or spontaneous action potential patterns. The absence of differences between ON and OFF activity patterns is unlike the differences that arise in ferrets. In contrast to the ferret, the ON and OFF target neurons in the mouse are organized in a random pattern, not layers. This supports the hypothesis that the absence of systematic differences in activity results in the nonlayered distribution of retinogeniculate connections.     

GABA(A) receptors containing the α2 subunit are critical for direction-selective inhibition in the retina

Far from being a simple sensor, the retina actively participates in processing visual signals. One of the best understood aspects of this processing is the detection of motion direction. Direction-selective (DS) retinal circuits include several subtypes of ganglion cells (GCs) and inhibitory interneurons, such as starburst amacrine cells (SACs). Recent studies demonstrated a surprising complexity in the arrangement of synapses in the DS circuit, i.e. between SACs and DS ganglion cells. Thus, to fully understand retinal DS mechanisms, detailed knowledge of all synaptic elements involved, particularly the nature and localization of neurotransmitter receptors, is needed. Since inhibition from SACs onto DSGCs is crucial for generating retinal direction selectivity, we investigate here the nature of the GABA receptors mediating this interaction. We found that in the inner plexiform layer (IPL) of mouse and rabbit retina, GABA(A) receptor subunit α2 (GABA(A)R α2) aggregated in synaptic clusters along two bands overlapping the dendritic plexuses of both ON and OFF SACs. On distal dendrites of individually labeled SACs in rabbit, GABA(A)R α2 was aligned with the majority of varicosities, the cell's output structures, and found postsynaptically on DSGC dendrites, both in the ON and OFF portion of the IPL. In GABA(A)R α2 knock-out (KO) mice, light responses of retinal GCs recorded with two-photon calcium imaging revealed a significant impairment of DS responses compared to their wild-type littermates. We observed a dramatic drop in the proportion of cells exhibiting DS phenotype in both the ON and ON-OFF populations, which strongly supports our anatomical findings that α2-containing GABA(A)Rs are critical for mediating retinal DS inhibition. Our study reveals for the first time, to the best of our knowledge, the precise functional localization of a specific receptor subunit in the retinal DS circuit.     

High glucose levels impact visual response properties of retinal ganglion cells in C57 mice—An <Emphasis Type="Italic">in vitro</Emphasis> physiological study

This study investigated visual response properties of retinal ganglion cells (RGCs) under high glucose levels. Extracellular single-unit responses of RGCs from mouse retinas were recorded. And the eyecup was prepared as a flat mount in a recording chamber and superfused with Ames medium. The averaged RF size of the ON RGCs (34.1±2.9, n=14) was significantly smaller than the OFF RGCs under the HG (49.3±0.3, n=12) (P<0.0001) conditions. The same reduction pattern was also observed in the osmotic control group (HM) between ON and OFF RGCs (P<0.0001). The averaged luminance threshold (LT) of ON RGCs increased significantly under HG or HM (HG: P<0.0001; HM: P<0.0002). OFF RGCs exhibited a similar response pattern under the same conditions (HG: P<0.01; HM: P<0.0002). The averaged contrast gain of ON cells was significantly lower than that of OFF cells with the HM treatment (P<0.015, unpaired Student’s t test). The averaged contrast gain of ON cells was significantly higher than OFF cells with the HG treatment (P<0.0001). The present results suggest that HG reduced receptive field center size, suppressed luminance threshold, and attenuated contrast gain of RGCs. The impact of HG on ON and OFF RGCs may be mediated via different mechanisms.     

Network Oscillations Drive Correlated Spiking of ON and OFF Ganglion Cells in the rd1 Mouse Model of Retinal Degeneration

Following photoreceptor degeneration, ON and OFF retinal ganglion cells (RGCs) in the rd-1/rd-1 mouse receive rhythmic synaptic input that elicits bursts of action potentials at ∼10 Hz. To characterize the properties of this activity, RGCs were targeted for paired recording and morphological classification as either ON alpha, OFF alpha or non-alpha RGCs using two-photon imaging. Identified cell types exhibited rhythmic spike activity. Cross-correlation of spike trains recorded simultaneously from pairs of RGCs revealed that activity was correlated more strongly between alpha RGCs than between alpha and non-alpha cell pairs. Bursts of action potentials in alpha RGC pairs of the same type, i.e. two ON or two OFF cells, were in phase, while bursts in dissimilar alpha cell types, i.e. an ON and an OFF RGC, were 180 degrees out of phase. This result is consistent with RGC activity being driven by an input that provides correlated excitation to ON cells and inhibition to OFF cells. A2 amacrine cells were investigated as a candidate cellular mechanism and found to display 10 Hz oscillations in membrane voltage and current that persisted in the presence of antagonists of fast synaptic transmission and were eliminated by tetrodotoxin. Results support the conclusion that the rhythmic RGC activity originates in a presynaptic network of electrically coupled cells including A2s via a Na⁺-channel dependent mechanism. Network activity drives out of phase oscillations in ON and OFF cone bipolar cells, entraining similar frequency fluctuations in RGC spike activity over an area of retina that migrates with changes in the spatial locus of the cellular oscillator.     

Modelling intrinsic electrophysiological properties of ON and OFF retinal ganglion cells

ON and OFF retinal ganglion cells (RGCs) display differences in their intrinsic electrophysiology: OFF cells maintain spontaneous activity in the absence of any input, exhibit subthreshold membrane potential oscillations, rebound excitation and burst firing; ON cells require excitatory input to drive their activity and display none of the aforementioned phenomena. The goal of this study was to identify and characterize ionic currents that explain these intrinsic electrophysiological differences between ON and OFF RGCs. A mathematical model of the electrophysiological properties of ON and OFF RGCs was constructed and validated using published patch-clamp data from isolated intact mouse retina. The model incorporates three ionic currents hypothesized to play a role in generating behaviors that are different between ON and OFF RGCs. These currents are persistent Na⁺, I _NaP, hyperpolarization-activated, I _h, and low voltage activated Ca^2 +, I _T, currents. Using computer simulations of Hodgkin-Huxley type neuron with a single compartment model we found two distinct sets of I _NaP, I _h, I _T conductances that correspond to ON and OFF RGCs populations. Simulations indicated that special properties of I _T explain the differences in intrinsic electrophysiology between ON and OFF RGCs examined here. The modelling shows that the maximum conductance of I _T is higher in OFF than in ON cells, in agreement with recent experimental data.     

Morphological and functional organization of ON and OFF pathways in the adult newt retina

Morphological and functional organization of ON and OFF pathways in the adult newt retina were examined by intracellular recording and staining techniques and immunohistochemistry. Synaptotagmin immunoreactivity discriminated three broad bands within the IPL: the distal band (sublamina I), the middle band (sublamina II) consisting of two dense punctate bands (sublaminae II(a) and II(b)), and proximal band (sublamina III). The Lucifer-yellow labeled OFF amacrine and ganglion cells send their processes mainly in sublamina I and/or II(a) where OFF bipolar cells extend their axon terminals, while ON amacrine and ganglion cells send their processes in sublamina III and/or II(b) where ON bipolar cells extend their axon terminals. Processes of ON-OFF amacrine and ganglion cells ramify broadly in the whole thickness of the IPL. Many bipolar cells responded to light spot with a transient hyperpolarization at both light onset and offset. They are probably subtypes of ON bipolar cells, because their axon terminals branch mainly in sublaminae III and/or II(b), although a few cells ramified the axon at both sublaminae II(a) and III. Two immunohistochemical markers for bipolar cells, PKC and RB-1, identified axon terminals in sublaminae III and/or II(b). From the ramification pattern of axon terminal, they are probably subtypes of ON bipolar cells. ChAT-ir amacrine cells ramified their dendrites in either sublamina I or II(b). Altogether, present studies support the general idea of segregation of ON and OFF pathways in sublaminae a and b of the IPL.     

Synaptic and voltage-gated currents in interplexiform cells of the tiger salamander retina

We have correlated the membrane properties and synaptic inputs of interplexiform cells (IPCs) with their morphology using whole-cell patch-clamp and Lucifer yellow staining in retinal slices. Three morphological types were identified: (a) a bistratified IPC with descending processes ramifying in both sublaminas a and b of the inner plexiform layer (IPL), and an ascending process that branched in the outer plexiform layer (OPL) and originated from the soma, (b) another bistratified IPC with descending processes ramifying in both sublaminas a and b, and an ascending process that branched in the OPL and originated directly from IPC processes in the IPL, and (c) a monostratified IPC with a descending process ramifying over large lateral extents within the most distal stratum of the IPL, and sending an ascending process to the OPL with little branching. Similar voltage- gated currents were measured in all three types including: (a) a transient inward sodium current, (b) an outward potassium current, and (c) an L-type calcium current. All cells generated multiple spikes with frequency increasing monotonically with the magnitude of injected current. The IPCs that send their descending processes into both sublaminas of the IPL (bistratified) receive excitatory synaptic inputs at both light ON and OFF that decay with a time constant of approximately 1.3 s. Slowly decaying excitation at both ON and OFF suggests that bistratified IPCs may spike continuously in the presence of a dynamic visual environment.     

The effect of morphology upon electrophysiological responses of retinal ganglion cells: simulation results

Retinal ganglion cells (RGCs) display differences in their morphology and intrinsic electrophysiology. The goal of this study is to characterize the ionic currents that explain the behavior of ON and OFF RGCs and to explore if all morphological types of RGCs exhibit the phenomena described in electrophysiological data. We extend our previous single compartment cell models of ON and OFF RGCs to more biophysically realistic multicompartment cell models and investigate the effect of cell morphology on intrinsic electrophysiological properties. The membrane dynamics are described using the Hodgkin - Huxley type formalism. A subset of published patch-clamp data from isolated intact mouse retina is used to constrain the model and another subset is used to validate the model. Two hundred morphologically distinct ON and OFF RGCs are simulated with various densities of ionic currents in different morphological neuron compartments. Our model predicts that the differences between ON and OFF cells are explained by the presence of the low voltage activated calcium current in OFF cells and absence of such in ON cells. Our study shows through simulation that particular morphological types of RGCs are capable of exhibiting the full range of phenomena described in recent experiments. Comparisons of outputs from different cells indicate that the RGC morphologies that best describe recent experimental results are ones that have a larger ratio of soma to total surface area.     

Blocking Retinal Chloride Co-Transporters KCC2 and NKCC: Impact on Direction Selective ON and OFF Responses in the Rat's Nucleus of the Optic Tract

In the present study we investigated in vivo the effects of pharmacological manipulation of retinal processing on the response properties of direction selective retinal slip cells in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN), the key visuomotor interface in the pathway underlying the optokinetic reflex. Employing a moving visual stimulus consisting of either a large dark or light edge we could differentiate direction selective ON and OFF responses in retinal slip cells. To disclose the origin of the retinal slip cells' unexpected OFF response we selectively blocked the retinal ON channels and inactivated the visual cortex by cooling. Cortical cooling had no effect on the direction selectivity of the ON or the OFF response in NOT-DTN retinal slip cells. Blockade of the retinal ON channel with APB led to a loss of the ON and, to a lesser degree, of the OFF response and a reduction in direction selectivity. Subsequent blocking of GABA receptors in the retina with picrotoxin unmasked a vigorous albeit direction unselective OFF response in the NOT-DTN. Disturbing the retinal chloride homeostasis by intraocular injections of bumetanide or furosemide led to a loss of direction selectivity in both the NOT-DTN's ON and the OFF response due to a reduced response in the neuron's preferred direction under bumetanide as well as under furosemide and a slightly increased response in the null direction under bumetanide. Our results indicate that the direction specificity of retinal slip cells in the NOT-DTN of the rat strongly depends on direction selective retinal input which depends on intraretinal chloride homeostasis. On top of the well established input from ON center direction selective ganglion cells we could demonstrate an equally effective input from the retinal OFF system to the NOT-DTN.     

Effect of 2-amino-4-phosphonobutyrate on the OFF responses of frog retinal ganglion cells and local ERG after glycinergic blockade

Perfusion with the ON channel blocker 2-amino-4-phosphonobutyrate (APB) of dark adapted frog eyecups not only abolished the ganglion cells' (GC) ON responses and the ERG b-wave, but markedly potentiated the OFF responses of ON-OFF and phasic OFF-GCs and the d-wave amplitude of simultaneously recorded local ERG. Glycinergic blockade by strychnine prevented this potentiating effect in 31 out of 69 GCs, but did not change it at all in the other cells. At the same time the d-wave potentiation was preserved during the glycinergic blockade in all eyecups. The results indicate that glycinergic transmission is involved in the inhibition exerted from ON upon OFF channel in some but not all frog retinal GCs.     

Axonal Synapses Utilize Multiple Synaptic Ribbons in the Mammalian Retina

In the mammalian retina, bipolar cells and ganglion cells which stratify in sublamina a of the inner plexiform layer (IPL) show OFF responses to light stimuli while those that stratify in sublamina b show ON responses. This functional relationship between anatomy and physiology is a key principle of retinal organization. However, there are at least three types of retinal neurons, including intrinsically photosensitive retinal ganglion cells (ipRGCs) and dopaminergic amacrine cells, which violate this principle. These cell types have light-driven ON responses, but their dendrites mainly stratify in sublamina a of the IPL, the OFF sublayer. Recent anatomical studies suggested that certain ON cone bipolar cells make axonal or ectopic synapses as they descend through sublamina a, thus providing ON input to cells which stratify in the OFF sublayer. Using immunoelectron microscopy with 3-dimensional reconstruction, we have identified axonal synapses of ON cone bipolar cells in the rabbit retina. Ten calbindin ON cone bipolar axons made en passant ribbon synapses onto amacrine or ganglion dendrites in sublamina a of the IPL. Compared to the ribbon synapses made by bipolar terminals, these axonal ribbon synapses were characterized by a broad postsynaptic element that appeared as a monad and by the presence of multiple short synaptic ribbons. These findings confirm that certain ON cone bipolar cells can provide ON input to amacrine and ganglion cells whose dendrites stratify in the OFF sublayer via axonal synapses. The monadic synapse with multiple ribbons may be a diagnostic feature of the ON cone bipolar axonal synapse in sublamina a. The presence of multiple ribbons and a broad postsynaptic density suggest these structures may be very efficient synapses. We also identified axonal inputs to ipRGCs with the architecture described above.     

Crossover inhibition in the retina: circuitry that compensates for nonlinear rectifying synaptic transmission

In the mammalian retina, complementary ON and OFF visual streams are formed at the bipolar cell dendrites, then carried to amacrine and ganglion cells via nonlinear excitatory synapses from bipolar cells. Bipolar, amacrine and ganglion cells also receive a nonlinear inhibitory input from amacrine cells. The most common form of such inhibition crosses over from the opposite visual stream: Amacrine cells carry ON inhibition to the OFF cells and carry OFF inhibition to the ON cells (”crossover inhibition”). Although these synapses are predominantly nonlinear, linear signal processing is required for computing many properties of the visual world such as average intensity across a receptive field. Linear signaling is also necessary for maintaining the distinction between brightness and contrast. It has long been known that a subset of retinal outputs provide exactly this sort of linear representation of the world; we show here that rectifying (nonlinear) synaptic currents, when combined thorough crossover inhibition can generate this linear signaling. Using simple mathematical models we show that for a large set of cases, repeated rounds of synaptic rectification without crossover inhibition can destroy information carried by those synapses. A similar circuit motif is employed in the electronics industry to compensate for transistor nonlinearities in analog circuits.     

Environmental enrichment effects on development of retinal ganglion cell dendritic stratification require retinal BDNF

A well-known developmental event of retinal maturation is the progressive segregation of retinal ganglion cell (RGC) dendrites into a and b sublaminae of the inner plexiform layer (IPL), a morphological rearrangement crucial for the emergence of the ON and OFF pathways. The factors regulating this process are not known, although electrical activity has been demonstrated to play a role. Here we report that Environmental Enrichment (EE) accelerates the developmental segregation of RGC dendrites and prevents the effects exerted on it by dark rearing (DR). Development of RGC stratification was analyzed in a line of transgenic mice expressing plasma-membrane marker green fluorescent protein (GFP) under the control of Thy-1 promoter; we visualized the a and b sublaminae of the IPL by using an antibody selectively directed against a specific marker of cholinergic neurons. EE precociously increases Brain Derived Neurotrophic Factor (BDNF) in the retina, in parallel with the precocious segregation of RGC dendrites; in addition, EE counteracts retinal BDNF reduction in DR retinas and promotes a normal segregation of RGC dendrites. Blocking retinal BDNF by means of antisense oligos blocks EE effects on the maturation of RGC dendritic stratification. Thus, EE affects the development of RGC dendritic segregation and retinal BDNF is required for this effect to take place, suggesting that BDNF could play an important role in the emergence of the ON and OFF pathways.