Retinal development has long been considered to be insensitive to experience. Recent evidences challenging this notion have come from works showing that DR can influence refinement of ON and OFF pathways in the retina 
and that an increased stimulation, such as that provided by EE, can affect the development of retinal visual responses 
In the present work we show that EE accelerates the developmental segregation of RGC dendrites and prevents the blockade of this maturational remodelling caused by DR.
Our results, as well as confirming the susceptibility of the developing retina to experience, increase our knowledge on EE effects on the development of sensory systems and show for the first time that a manipulation as simple as enriching the environment affects the development of RGC dendritic segregation, cardinal feature of retinal circuitry development.
The effects of EE on RGC dendritic stratification are evident already at P10, that is, before eye opening. This precocious action of EE on retinal development is in accordance with our recent results 
showing that exposure to EE up to P10 is sufficient to trigger the acceleration of retinal visual responses.
This, together with the result that EE leads to normal RGC dendritic stratification in DR mice, suggests that the factors EE acts upon to trigger the refinement of RGC circuitry do not require visual experience, although visual experience may modulate their expression.
Our results identify one of these factors as retinal BDNF. We present three evidences in favour of BDNF being a key factor mediating EE effects on the morphological remodelling of RGC dendritic arborizations, two correlative and one causal. BDNF is precociously increased in the retina of EE mice, as recently found for EE rats 
, in parallel with the precocious segregation of RGC dendrites promoted by EE; BDNF expression, which is reduced in DR retinas [23, our present results], is normal in the retinas of dark reared EE animals, in parallel with the normal segregation of RGC dendrites promoted by EE; the causal evidence is that blocking retinal BDNF expression by means of antisense oligonucleotides prevents EE from accelerating this developmental segregation.
Thus, BDNF increase in EE retinas seems necessary for the effects of EE on RGC dendritic development to take place, indicating that BDNF plays an important role in regulating the developmental transition of RGC dendrites from bi- to mono-stratified.
It is important to underline that the expression of BDNF is affected by EE within the first days of postnatal life when pups are still immobile and dependent on the mother. Indeed, we have found that BDNF protein level is enhanced very precociously (around P8) in the retina of enriched mice. This result is in agreement with our previous study indicating that BDNF protein level is enhanced at very early age by EE: at P7 in the visual cortex of enriched mice 
and at P10 in the retina of enriched rats 
. A possible explanation for the precocious enhancement of BDNF is suggested by the combination of two sets of results; we have recently shown that EE animals are subjected to higher levels of maternal care 
, while Liu et al. 
have shown that high levels of maternal care enhance BDNF mRNA expression in rat hippocampus.
How could changes in BDNF regulate RGC structural refinement?
BDNF could act directly on RGCs in an autocrine fashion. It is known that mRNA for BDNF and its functional receptor, TrkB, are present in RGCs 
and that RGCs are sensitive to BDNF. In particular, BDNF shapes dendritic morphology 
and data from the Xenopus have shown that retinal BDNF reduces RGC dendritic arborization 
An interesting possibility is that BDNF control on RGC dendritic developmental remodelling takes place through an action on the synaptic transmission between bipolar cells and RGCs. Afferent input of bipolar cells has been demonstrated to play a critical role in the developmental segregation of RGC dendrites. The bipolar terminals are stratified even before ribbon synapses appear in the IPL 
and even in the absence of RGCs 
suggesting that bipolar cells stratify their axon terminals in the IPL responding to molecular cues. The stratification process of RGC dendrites starts at a time when bipolar cells form the first synaptic contacts with RGCs. In addition, injections of APB, a group III metabotropic glutamate receptor agonist, that hyperpolarizes both ON cone and rod bipolar cells preventing their release of glutamate, blocks RGC dendritic stratification 
. Although specific TrkB labelling was not reported for bipolar cells, making an action of retinal BDNF on these cells unlikely, BDNF might play a role in the development of synaptic transmission between bipolar and RGCs promoting the activation of functional NMDA receptors in RGCs 
In addition to the glutamatergic transmission between bipolar and RGCs, also cholinergic transmission, originated by the cholinergic starburst amacrine cells, may play a role in the developmental remodelling of RGC dendritic stratification. The ON-OFF stratification in RGCs is altered in mice lacking the β2 nicotinic receptor subunit 
. ChAT positive processes stratify into two separate bands, corresponding to sublaminae a and b in the IPL, very early in the developing retina 
, suggesting that starburst neurites could provide local cues for RGC dendrites in the IPL. Recently, it has also been shown that a moderate rearranging of the spatial organization of the two cholinergic bands in the IPL occurs following visual deprivation 
, a manipulation which delays the maturation of RGC dendritic stratification 
. However, cell specific TrkB labelling was not reported for cholinergic amacrine cells and the morphology of the plexuses of cholinergic projections is unchanged by exogenous BDNF delivered from P8 to P14 
Thus, a direct action of BDNF onto cholinergic amacrine cells seems unlikely; however an indirect action mediated by dopaminergic amacrine cells is possible.
Dopaminergic amacrine cells express TrkB receptor and BDNF clearly controls the development of the retinal dopaminergic network 
. The projections of dopaminergic cells have been shown to innervate the IPL sublaminae with a temporal order overlapping the time period during which glutamatergic and cholinergic systems begin to mature and RGC dendrites segregate 
. Dopaminergic amacrine cells have neuromodulatory effects on RGCs via amacrine intermediaries, particularly the AII cells 
. Recently, an action of dopamine on the acetylcholine release in the retina has been reported 
, suggesting that the retinal dopaminergic tone could affect the cholinergic transmission, and thus influence RGC dendritic stratification.