Visual Cortex

Visual information, initially encoded by the RGCs, is propagated to morphologically distinct layers in the LGN of the thalamus. By way of the geniculocortical pathway, LGN neurons send terminal arbors that form dense clusters in layer 4 of the VC. The development of thalamic-cortical synapses exhibit several characteristic features: (1) ocular dominance (OD): pyramidal neurons, particularly those in layer 4, respond preferentially to inputs from one eye. In cat and primates, cells that respond to one eye are organized into alternating, eye-specific columns; (2) activity-dependent synaptic competition: in cells that receive inputs from both eyes, the strength of the synaptic connection depends on the activity of the thalamic inputs from a specific eye; and (3) critical period (CP): this activity-dependent modulation of cortical synapse formation occurs in a defined period of time during development. These features have allowed scientists to use two powerful experimental approaches. One is monocular deprivation (MD), namely manipulations that block the neuronal activity of one eye (e.g., eyelid suture) during CP. A striking effect of MD is to cause a shift of OD toward the nondeprived eye. The second commonly used approach is dark rearing (DR), namely to block the activity of both eyes. This manipulation delays the formation of OD and therefore postpones CP.

These interesting features of VC synapses strongly suggest that RGC inputs from the two eyes compete for factors produced in the postsynaptic cells in an activity-dependent manner. To determine whether a factor is critically involved in the development of OD, several criteria should be fulfilled. This factor should be produced in a limited amount in the cortex, and its production (or responsiveness)

should be controlled by the electrical activity of input eyes. Thalamic afferents should be responsive (express receptors) to the factor. Experimentally, application (or overexpression) of the factor should rescue the OD shift induced by MD, and enhance synapse formation in the VC and shorten CP.

Studies by Maffei and his colleagues suggest that NGF is the critical factor in the rat VC. Intraventricular infusion of NGF during the CP abolished the physiological shift in OD toward the nondeprived eye following MD86 as well as prevented the shrinkage of LGN cell bodies87,88. Conversely, administration of antibodies against NGF extended the CP89 and also induced shrinkage of LGN cells90. NGF also prevented some of the deficits induced by DR, allowing normal development of VC synapses91,92. However, NGF is poorly expressed in the VC. Furthermore the NGF receptor TrkA is only expressed in cholinergic afferents that stem from the basal forebrain, but not in the axons of geniculate neurons93. Collectively, these observations weaken the argument that NGF is a factor that directly controls OD formation.

More compelling evidence supports TrkB ligands as the critical factor in the VC. Several studies highlight a role for BDNF and perhaps NT-4, through activation of TrkB, in controlling the competitive interactions between geniculate inputs to the VC. TrkB receptor is highly expressed by LGN neurons during early postnatal life94-97. Both BDNF98 and NT-499 mRNAs are detected in layer 4 pyramidal neurons. Moreover, BDNF expression increases rapidly after eye opening98,100. Lid suture or intravitreal injection of TTX induced a downregulation of BDNF expression94,98. Thus, BDNF mRNA levels correlate with the activity level of postsynaptic visual cortical neurons. More importantly, when TrkB ligands were infused into kitten VC during the CP, LGN axons failed to segregate into OD columns near the site of infusion101. However when BDNF infusion was performed on adult cats, OD formation was unaffected102. Therefore the sensitivity of visual cortical cells to BDNF appears to be restricted to the CP. Administration of NT-4 into VC prevented the OD shift103 as well as the shrinkage of LGN neurons normally associated with the deprived eye after MD104. Conversely, administration of TrkB-IgG, a scavenger for BDNF/NT-4, inhibited segregation of LGN axons near the site of infusion105 . These experiments support a model in which activity-dependent expression and/or uptake of TrkB ligands, driven by eye-specific LGN axons, underlies the maturation and stabilization of eye-specific synapses, and therefore the segregation of OD.

In addition to its direct role in the formation of excitatory synapses between LGN axons and pyramidal neurons, BDNF also regulates GABAergic synapses. Mice deficient for GAD-65, an enzyme required for GABA synthesis, which does not have fast synaptic inhibition, were not sensitive to MD106. In these animals, the OD shift in favor of the open eye normally observed after monocular deprivation did not occur but was reversed by the administration of diazepam, a GABAergic use-dependent agonist106. These results suggest an important role for GABAergic interneurons in the development of OD. In the cortex, GABAergic neurons express TrkB but not BDNF. Application of BDNF enhances GABA release and promotes the differentiation of GABAergic neurons. Mice that lack BDNF have significantly reduced GABAergic markers, such as parvalbumin, in the cortex107. On the other hand, maturation of GABAergic inhibition is accelerated in the VC of BDNF-overexpressing mice108. As a result, these BDNF over-expressing mice have an earlier and shorter CP that is sensitive to MD.

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