Homosynaptic Long-term Depression Research Articles

CaMKII T286 phosphorylation has distinct essential functions in three forms of long-term plasticity

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear. Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation (pT286), which induces Ca2+-independent autonomous kinase activity. In addition, we compared the role of pT286 among three forms of long-term plasticity (NMDAR-dependent LTP and LTD, and mGluR-dependent LTD) using simultaneous live imaging of endogenous CaMKII together with synaptic marker proteins. We determined that after LTP stimuli, pT286 autophosphorylation accelerated CaMKII movement to excitatory synapses. After NMDAR-LTD stimuli, pT286 was strictly required for any movement to inhibitory synapses. Similar to NMDAR-LTD, we found the mGluR-LTD stimuli did not induce CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, we demonstrate that the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Thus, despite its prominent role in LTP, we conclude that CaMKII T286 autophosphorylation is also required for both major forms of hippocampal LTD, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

Adult-Onset Hypothyroidism Alters the Metaplastic Properties of Dentate Granule Cells by Decreasing Akt Phosphorylation.

The expression of homosynaptic long-term depression (LTD) governs the subsequent induction of long-term potentiation (LTP) at hippocampal synapses. This process, called metaplasticity, is associated with a transient increase in the levels of several kinases, such as extracellular signal-regulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and Akt kinase. It has been increasingly realized that the chemical changes in the hippocampus caused by hypothyroidism may be the key underlying causes of the learning deficits, memory loss, and impaired LTP associated with this disease. However, the functional role of thyroid hormones in the "plasticity of synaptic plasticity" has only begun to be elucidated. To address this issue, we sought to determine whether the administration of 6-n-propyl-2-thiouracil (PTU) alters the relationship between priming and the induction of subsequent LTP and related signaling molecules. The activation of ERK1/2, JNK, and Akt was measured in the hippocampus at least 95min after priming onset. We found that priming stimulation at 5Hz for 3s negatively impacted the induction of LTP by subsequent tetanic stimulation in hypothyroid animals, as manifested by a more rapid decrease in the fEPSP slope and population spike amplitude. This phenomenon was accompanied by lower levels of phosphorylated Akt in the surgically removed hippocampus of the hypothyroid rats compared to the euthyroid rats. The metaplastic response and the expression of these proteins in the 1-Hz-primed hippocampus were not different between the two groups. These observations suggest that decreased PI3K/Akt signaling may be involved in the compromised metaplastic regulation of LTP observed in hypothyroidism, which may account for the learning difficulties/cognitive impairments associated with this condition.

Arc restores juvenile plasticity in adult mouse visual cortex

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here, we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild-type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.

Starting from the Ground State Up: Factors Influencing Synaptic Plasticity

To many, long-term potentiation (LTP) and long-term depression (LTD) represent two forms of synaptic plasticity that play an obligate role in the encoding and storage of memory within the mammalian hippocampus. Long-term potentiation was first described by Tim Bliss and Terje Lomo in 1973 in the rabbit dentate gyrus (1), and although a form of heterosynaptic LTD was described in 1977 (2), most neuroscientists are more familiar with the homosynaptic LTD first described by Serena Dudek and Mark Bear (3).

Endogenous inhibition of hippocampal LTD and depotentiation by vasoactive intestinal peptide VPAC1 receptors.

Vasoactive intestinal peptide (VIP), an important modulator of hippocampal synaptic transmission, influences exploration and hippocampal-dependent learning in rodents. Homosynaptic long-term depression (LTD) and depotentiation are two plasticity phenomena implicated in learning of behavior flexibility and spatial novelty detection. In this study, we investigated the influence of endogenous VIP on LTD and depotentiation induced by low-frequency stimulation (1 Hz, 900 pulses) of the hippocampal CA1 area in vitro in juvenile and young adult rats, respectively. LTD and depotentiation were enhanced by the VIP receptor antagonist Ac-Tyr(1) , D-Phe(2) GRF (1-29), and the selective VPAC1 receptor antagonist, PG 97-269, but not the selective VPAC2 receptor antagonist, PG 99-465. This action was mimicked by an anti-VIP antibody, suggesting that VIP, and not pituitary adenylate cyclase-activating polypeptide (PACAP), is the endogenous mediator of these effects. Selective inhibition of PAC1 receptors with PACAP (6-38) enhanced depotentiation, but not LTD. VPAC1 receptor blockade also revealed LTD in young adult rats, an effect abolished by the GABAA antagonist bicuculline, evidencing an involvement of GABAergic transmission. We conclude that inhibition of LTD and depotentiation by endogenous VIP occurs through VPAC1 receptor-mediated mechanisms and suggest that disinhibition of pyramidal cell dendrites is the most likely physiological mechanism underlying this effect. As such, VPAC1 receptor ligands may be considered promising pharmacological targets for treatment of cognitive dysfunction in diseases involving altered GABAergic circuits and pathological saturation of LTP/LTD like Down's syndrome and temporal lobe epilepsy.

Early life stress alters synaptic modification range in the rat lateral amygdala

The influence of exposure to early adversity on emotional learning later in life remains poorly understood. Long-term potentiation (LTP) in the cortico-amygdalar and thalamo-amygdalar pathways has been postulated to provide a mechanism of synaptic modifications underlying fear learning and memory. These synapses also express homosynaptic long-term depression (LTD). Here we examined the effects of maternal separation stress on the extent of LTP and LTD which could be induced in the lateral amygdala (LA) of adolescent rats. Rat pups were subjected to maternal separation (MS, 3 h/day) on post-natal days 1-21. Field potentials were recorded ex vivo from slices containing the LA, which were prepared from adolescent males. Saturating levels of LTP and LTD were induced using repeated sequences of theta-burst stimulation and low frequency stimulation, respectively. An impairment of the maximum LTP and an enhancement of the maximum LTD were observed in the cortical input in slices prepared from MS-subjected rats. In the thalamic input, both the maximum LTP and the maximum LTD were reduced when compared to control animals. Thus, in the cortico-amygdalar pathway MS stress shifted the potential for bidirectional synaptic modification toward LTD but it shrank the synaptic modification range in the thalamo-amygdalar pathway.

Low-frequency stimulation induces long-term depression and slow onset long-term potentiation at perforant path-dentate gyrus synapses in vivo

The expression of homosynaptic long-term depression (LTD) is thought to mediate a crucial role in sustaining memory function. Our in vivo investigations of LTD expression at lateral (LPP) and medial perforant path (MPP) synapses in the dentate gyrus (DG) corroborate prior demonstrations that PP-DG LTD is difficult to induce in intact animals. In freely moving animals, LTD expression occurred inconsistently among LPP-DG and MPP-DG responses. Interestingly, following acute electrode implantation in anesthetized rats, low-frequency stimulation (LFS; 900 pulses, 1 Hz) promotes slow-onset LTP at both MPP-DG and LPP-DG synapses that utilize distinct induction mechanisms. Systemic administration of the N-methyl-d-aspartate (NMDA) receptor antagonist (+/-)-cyclopiperidine-6-piperiperenzine (CPP; 10 mg/kg) 90 min before LFS selectively blocked MPP-DG but not LPP-DG slow onset LTP, suggesting MPP-DG synapses express a NMDA receptor-dependent slow onset LTP whereas LPP-DG slow onset LTP induction is NMDA receptor independent. In experiments where paired-pulse LFS (900 paired pulses, 200-ms paired-pulse interval) was used to induce LTD, paired-pulse LFS of the LPP resulted in rapid onset LTP of DG responses, whereas paired-pulse LFS of the MPP induced slow onset LTP of DG responses. Although LTD observations were very rare following acute electrode implantation in anesthetized rats, LPP-DG LTD was demonstrated in some anesthetized rats with previously implanted electrodes. Together, our data indicate in vivo PP-DG LTD expression is an inconsistent phenomenon that is primarily observed in recovered animals, suggesting perturbation of the dentate through surgery-related tissue trauma influences both LTD incidence and LTP induction at PP-DG synapses in vivo.

Activation of Synaptic Group II Metabotropic Glutamate Receptors Induces Long-Term Depression at GABAergic Synapses in CNS Neurons

Metabotropic glutamate receptor (mGluR)-dependent homosynaptic long-term depression (LTD) has been studied extensively at glutamatergic synapses in the CNS. However, much less is known about heterosynaptic long-term plasticity induced by mGluRs at inhibitory synapses. Here we report that pharmacological or synaptic activation of group II mGluRs (mGluR II) induces LTD at GABAergic synapses without affecting the excitatory glutamatergic transmission in neurons of the chicken cochlear nucleus. Coefficient of variation and failure rate analysis suggested that the LTD was expressed presynaptically. The LTD requires presynaptic spike activity, but does not require the activation of NMDA receptors. The classic cAMP-dependent protein kinase A signaling is involved in the transduction pathway. Remarkably, blocking mGluR II increased spontaneous GABA release, indicating the presence of tonic activation of mGluR II by ambient glutamate. Furthermore, synaptically released glutamate induced by electrical stimulations that concurrently activated both the glutamatergic and GABAergic pathways resulted in significant and constant suppression of GABA release at various stimulus frequencies (3.3, 100, and 300 Hz). Strikingly, low-frequency stimulation (1 Hz, 15 min) of the glutamatergic synapses induced heterosynaptic LTD of GABAergic transmission, and the LTD was blocked by mGluR II antagonist, indicating that synaptic activation of mGluR II induced the LTD. This novel form of long-term plasticity in the avian auditory brainstem may play a role in the development as well as in temporal processing in the sound localization circuit.

COMPUTATIONAL MODELING OF LONG-TERM DEPRESSION OF SYNAPTIC WEIGHTS: INSIGHTS FROM STDP, METAPLASTICITY AND SPONTANEOUS ACTIVITY

Using the STDP rule with metaplasticity, we show that to evoke long- term depression (LTD) or depotentiation of synaptic weights in the spiking model of granule cell is not easy. This is in accordance with a number of experimental studies. On the other hand, heterosynaptic LTD which accompanies homosynaptic long-term potentiation (LTP) is induced readily both in the model as well as in experiments. We offer possible explanation of these phenomena from STDP, meta- plasticity and spontaneous activity. We suggest conditions under which it would be possible to induce homosynaptic LTD and depotentiation.

Activation Conditions for the Induction of Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal CA1 Pyramidal Cells

Two forms of homosynaptic long-term depression (LTD) are distinguished in hippocampal CA1 pyramidal cells, one which is NMDA receptor dependent and the other metabotropic glutamate receptor (mGluR) dependent. Although the molecular processes involved in mGluR-LTD are well characterized, the conditions of circuit activation required for its induction remain unclear. We show that mGluR-LTD cannot be induced in synaptically coupled CA3-CA1 pyramidal cell pairs. Experiments to address the underlying mechanisms indicate that, even when glutamate transporters are blocked, one presynaptic cell releases insufficient glutamate to evoke an mGluR-mediated current in a connected CA1 cell. These findings imply that extrasynaptic diffusion is not a limiting factor and are consistent with a sparse distribution of functional mGluRs in the dendritic tree of pyramidal cells. Thus, the discharge of multiple Schaffer collaterals to a targeted cell is necessary for mGluR-LTD. Our experiments indicate that approximately eight CA3 inputs to a CA1 pyramidal cell must be activated to induce mGluR-LTD.

Metaplasticity Governs Natural Experience-Driven Plasticity of Nascent Embryonic Brain Circuits

During embryogenesis, brain neurons receiving the same sensory input may undergo potentiation or depression. While the origin of variable plasticity in vivo is unknown, it plays a key role in shaping dynamic neural circuit refinement. Here, we investigate effects of natural visual stimuli on neuronal firing within the intact, awake, developing brain using calcium imaging of 100 s of central neurons in the Xenopus retinotectal system. We find that specific patterns of visual stimuli shift population responses toward either potentiation or depression in an N-methyl-D-aspartate receptor (NMDA-R)-dependent manner. In agreement with Bienenstock-Cooper-Munro metaplasticity, our results show that functional potentiation or depression can be predicted by individual neurons' specific receptive field properties and historic firing rates. Interestingly, this activity-dependent metaplasticity is itself NMDA-R dependent. Furthermore, network analysis reveals increased correlated firing of neurons that undergo potentiation. These findings implicate metaplasticity as a natural property regulating experience-dependent refinement of nascent embryonic brain circuits.

Enhanced homosynaptic LTD in cerebellar Purkinje cells of the dystrophic MDX mouse

The purpose was to study homosynaptic long-term depression (LTD) at the parallel fiber-Purkinje cell synapse in the mdx mouse, a murine model of the human dystrophinopathy, Duchenne muscular dystrophy (DMD), in order to examine whether the absence of dystrophin affects the induction and extent of this form of synaptic plasticity. Sharp intracellular electrodes were used to record electrically evoked excitatory postsynaptic potentials (EPSPs) from identified Purkinje cells in cerebellar slices. The early phase of homosynaptic LTD, 7-16 min postinduction, was the same in mdx and wildtype Purkinje cells; however, the late phase of LTD, 35-44 min, was significantly enhanced in mdx Purkinje cells. We hypothesize that this enhancement of the late phase of homosynaptic LTD may be due to a disruption of Ca(2+) homeostasis associated with the absence of the protein dystrophin. These findings may explain some of the central nervous system deficiencies reported in DMD boys.

Essential role for a long-term depression mechanism in ocular dominance plasticity

The classic example of experience-dependent cortical plasticity is the ocular dominance (OD) shift in visual cortex after monocular deprivation (MD). The experimental model of homosynaptic long-term depression (LTD) was originally introduced to study the mechanisms that could account for deprivation-induced loss of visual responsiveness. One established LTD mechanism is a loss of sensitivity to the neurotransmitter glutamate caused by internalization of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Although it has been shown that MD similarly causes a loss of AMPARs from visual cortical synapses, the contribution of this change to the OD shift has not been established. Using an herpes simplex virus (HSV) vector, we expressed in visual cortical neurons a peptide (G2CT) designed to block AMPAR internalization by hindering the association of the C-terminal tail of the AMPAR GluR2 subunit with the AP2 clathrin adaptor complex. We found that G2CT expression interferes with NMDA receptor (NMDAR)-dependent AMPAR endocytosis and LTD, without affecting baseline synaptic transmission. When expressed in vivo, G2CT completely blocked the OD shift and depression of deprived-eye responses after MD without affecting baseline visual responsiveness or experience-dependent response potentiation in layer 4 of visual cortex. These data suggest that AMPAR internalization is essential for the loss of synaptic strength caused by sensory deprivation in visual cortex.

Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex

As in other mammals with binocular vision, monocular lid suture in mice induces bidirectional plasticity: rapid weakening of responses evoked through the deprived eye followed by delayed strengthening of responses through the open eye. It has been proposed that these bidirectional changes occur through three distinct processes: first, deprived-eye responses rapidly weaken through homosynaptic long-term depression (LTD); second, as the period of deprivation progresses, the modification threshold determining the boundary between synaptic depression and synaptic potentiation becomes lower, favouring potentiation; and third, facilitated by the decreased modification threshold, open-eye responses are strengthened via homosynaptic long-term potentiation (LTP). Of these processes, deprived-eye depression has received the greatest attention, and although several alternative hypotheses are also supported by current research, evidence suggests that α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor endocytosis through LTD is a key mechanism. The change in modification threshold appears to occur partly through changes in N-methyl-d-aspartate (NMDA) receptor subunit composition, with decreases in the ratio of NR2A to NR2B facilitating potentiation. Although limited research has directly addressed the question of open-eye potentiation, several studies suggest that LTP could account for observed changes in vivo. This review will discuss evidence supporting this three-stage model, along with outstanding issues in the field.

Roles of Endocannabinoids in Heterosynaptic Long-Term Depression of Excitatory Synaptic Transmission in Visual Cortex of Young Mice

Tetanic stimulation of one of two afferent pathways converging to neurons in the visual cortex induces long-term depression (LTD) of synaptic transmission in the other, nonactivated pathway under a certain condition. This form of synaptic plasticity called heterosynaptic LTD (hetero-LTD) was not systematically investigated in previous studies, whereas homosynaptic LTD has been extensively studied. To determine whether hetero-LTD is induced in visual cortical slices of mice and, if so, through what mechanisms, we recorded EPSPs evoked in layer II/III neurons by alternating test stimulation of two sites in layer IV at 0.05 Hz. After theta-burst stimulation of one site, EPSPs evoked by test stimulation of the other site were depressed for a long time in most of the neurons, whereas homosynaptic long-term potentiation was induced at activated synapses. Such a hetero-LTD was induced in most mice at postnatal day 7-20 (P7-P20), but not induced in mice at P35-P41. Tests using the paired-pulse stimulation protocol and coefficient of variation analysis suggested that hetero-LTD was expressed at presynaptic sites. Pharmacological analysis indicated that this form of LTD was induced through activation of the type 5 of metabotropic glutamate receptors, not through the NMDA type of glutamate receptors. Additional analysis using a cannabinoid type 1 receptor agonist and an antagonist suggested that endocannabinoids (eCBs) are involved in this type of LTD. Moreover, results suggest that brain-derived neurotrophic factor, which may be released from strongly activated presynaptic sites, prevents eCBs from suppressing the release of transmitters from these sites.

-Adrenoreceptors Comprise a Critical Element in Learning-Facilitated Long-Term Plasticity

A novel spatial environment consists of several different types of information that may be encoded by cellular information storage mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). Arousal, mediated, for example, by activation of the noradrenergic system, is a critical factor in information acquisition and may enhance the encoding of novel spatial information. Using electrophysiological recordings of hippocampal responses in freely moving rats during spatial learning, we investigated the role of the beta-adrenoreceptor in Schaeffer collateral-CA1 synaptic plasticity. We found that novel exploration of spatial context facilitates induction of LTD that is inhibited by intracerebroventricular application of the beta-adrenoreceptor antagonist, propranolol. Long-lasting homosynaptic LTD, that was electrically induced by low-frequency stimulation, was unaffected by the antagonist. Although application of a beta-adrenoreceptor agonist (isoproterenol) did not affect electrically induced LTD, agonist application facilitated short-term depression (STD) into LTD and mimicked the augmentation, through spatial exploration, of STD into LTD. Exploration of a novel empty environment facilitated LTP that was prevented by application of propranolol. These results suggest that beta-adrenoreceptors may facilitate encoding of spatial information through synaptic plasticity in the hippocampus and that noradrenaline is a key factor in effective information acquisition.

“Heterosynaptic” LTD in the Dentate Gyrus of Anesthetized Rat Requires Homosynaptic Activity

Heterosynaptic long-term depression (LTD) is conventionally defined as occurring at synapses that are inactive during a time when neighboring synapses are activated by high-frequency stimulation. A new model that combines computational properties of both the Bienenstock, Cooper and Munro model and spike timing-dependent plasticity, however, suggests that such LTD actually may require presynaptic activity in the depressed pathway. We tested experimentally whether presynaptic activity is in fact necessary for previously described heterosynaptic LTD in lateral perforant path synapses in the dentate gyrus of urethane-anesthetized rats. As predicted by the model, procaine infusion into the lateral path fibers, sufficient to transiently block neural activity in this pathway, prevented the induction of LTD in the lateral path following medial path high-frequency stimulation. These data indicate that the previously described heterosynaptic LTD in the dentate gyrus in vivo is actually a form of homosynaptic LTD, requiring presynaptic activity in the depressed pathway.

Low‐frequency stimulation of the direct cortical input to area CA1 induces homosynaptic LTD and heterosynaptic LTP in the rat hippocampal–entorhinal cortex slice preparation

The entorhinal cortex (EC) innervates area CA1 and the subiculum directly via the portion of the perforant path, which originates from EC layer III cells referred to as direct cortical input (dCI), and indirectly via the trisynaptic loop through the dentate gyrus and area CA3. The dCI is of great importance as it mediates positional information for activation of place cells that is not prevented after interrupting information flow from area CA3 to CA1. In this study, we investigated the effects of low-frequency stimulation of the dCI on homo- and heterosynaptic plasticity in area CA1 and tested for the contribution of NMDA, GABA(A), GABA(B), kainate and group I mGlu receptors. We demonstrate that 1 Hz stimulation of the dCI induces homosynaptic long-term depression (LTD) and that 1 Hz stimulation of the dCI induces a long-lasting augmentation of stratum radiatum-induced population spikes in area CA1 (heterosynaptic long-term potentiation). Additionally we show that homosynaptic effects depend on activation of GABA(B) and kainate receptors, whereas the heterosynaptic effects are GABA(A) and mGlu receptor dependent.

Fractalkine/CX 3CL1 depresses central synaptic transmission in mouse hippocampal slices

This work reports the effect of chemokine fractalkine/CX 3CL1, an endogenous small peptide highly expressed in the central nervous system, on evoked synaptic responses investigated in mouse CA1 stratum radiatum using an electrophysiological approach. We report that in acute mouse hippocampal slices, superfusion of CX 3CL1 resulted in a reversible depression of the field excitatory postsynaptic potential (fEPSP) which developed within few seconds, increased for up to 10 min of application and disappeared within 30 min after the end of CX 3CL1 treatment. We also show that CX 3CL1-induced synaptic depression is (i) dose-dependent with IC 50 and n H values of 0.7 nM and 1, respectively, (ii) not associated with a change in paired-pulse facilitation, (iii) mediated through CX 3CL1 receptor (CX 3CR1), being absent in CX 3CR1 −/− mice and inhibited in wild-type mice by a specific blocking antibody, and (iv) occluded by the induction of homosynaptic long-term depression (LTD). We conclude that CX 3CL1 is a potent neuromodulator of the evoked excitatory synaptic transmission, sharing common mechanisms with LTD.

A Role for Retinal Brain-Derived Neurotrophic Factor in Ocular Dominance Plasticity

Visual deprivation is a classical tool to study the plasticity of visual cortical connections. After eyelid closure in young animals (monocular deprivation, MD), visual cortical neurons become dominated by the open eye, a phenomenon known as ocular dominance (OD) plasticity . It is commonly held that the molecular mediators of OD plasticity are cortically derived and that the retina is immune to the effects of MD . Recently, it has been reported that visual deprivation induces neurochemical, structural, and functional changes in the retina , but whether these retinal changes contribute to the effects of MD in the cortex is unknown. Here, we provide evidence that brain-derived neurotrophic factor (BDNF) produced in the retina influences OD plasticity. We found a reduction of BDNF expression in the deprived retina of young rats. We compensated this BDNF imbalance between the two eyes by either injecting exogenous BDNF in the deprived eye or reducing endogenous BDNF expression in the nondeprived eye. Both treatments were effective in counteracting the OD shift induced by MD. Retinal BDNF could also influence OD distribution in normal animals. These results show for the first time that OD plasticity is modulated by BDNF produced in the retina.