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During development, experience plays a crucial role in sculpting neuronal connections. Patterned neural activity guides formation of functional neural circuits through the selective stabilization of some synapses and the pruning of others. Activity-regulated factors are fundamental to this process, but their roles in synapse stabilization and maturation is still poorly understood. CPG15, encoded by the activity-regulated gene candidate plasticity gene 15, is a small, glycosylphosphatidylinositol (GPI)-linked, extracellular protein that promotes synapse stabilization. Here we show that global knock-out of cpg15 results in abnormal postnatal development of the excitatory network in visual cortex and an associated disruption in development of visual receptive field properties. In addition, whereas repeated stimulation induced potentiation and depression in wild-type mice, the depression was slower in cpg15 knock-out mice, suggesting impairment in short-term depression-like mechanisms. These findings establish the requirement for cpg15 in activity-dependent development of the visual system and demonstrate the importance of timely excitatory network development for normal visual function.

Visual circuits mature and are refined by sensory experience. However, significant gaps remain in our understanding how deprivation influences the development of visual acuity in mice. Here, we perform a longitudinal study assessing the effects of chronic deprivation on the development of the mouse subcortical and cortical visual circuits using a combination of behavioral optomotor testing, in vivo visual evoked responses (VEP) and single-unit cortical recordings. As previously reported, orientation tuning was degraded and onset of ocular dominance plasticity was delayed and remained open in chronically deprived mice. Surprisingly, we found that the development of optomotor threshold and VEP acuity can occur in an experience-independent manner, although at a significantly slower rate. Moreover, monocular deprivation elicited amblyopia only during a discrete period of development in the dark. The rate of recovery of optomotor threshold upon exposure of deprived mice to light confirmed a maturational transition regardless of visual input. Together our results revealed a dissociable developmental trajectory for visual receptive-field properties in dark-reared mice suggesting a differential role for spontaneous activity within thalamocortical and intracortical circuits.

A fine interplay exists between sensory experience and innate genetic programs leading to the sculpting of neuronal circuits during early brain development. Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the formation of critical periods and provide new strategies for increasing plasticity and adaptive change in adulthood.

Weak inhibition within visual cortex early in life prevents experience-dependent plasticity. Loss of responsiveness to an eye deprived of vision can be initiated prematurely by enhancing gamma-aminobutyric acid (GABA)-mediated transmission with benzodiazepines. Here, we use a mouse "knockin" mutation to alpha subunits that renders individual GABA type A (GABA(A)) receptors insensitive to diazepam to show that a particular inhibitory network controls expression of the critical period. Only alpha1-containing circuits were found to drive cortical plasticity, whereas alpha2-enriched connections separately regulated neuronal firing. This dissociation carries implications for models of brain development and the safe design of benzodiazepines for use in infants.

Neuronal circuits across several systems display remarkable plasticity to sensory input during postnatal development. Experience-dependent refinements are often restricted to well-defined critical periods in early life, but how these are established remains mostly unknown. A representative example is the loss of responsiveness in neocortex to an eye deprived of vision. Here we show that the potential for plasticity is retained throughout life until an inhibitory threshold is attained. In mice of all ages lacking an isoform of GABA (gamma-aminobutyric acid) synthetic enzyme (GAD65), as well as in immature wild-type animals before the onset of their natural critical period, benzodiazepines selectively reduced a prolonged discharge phenotype to unmask plasticity. Enhancing GABA-mediated transmission early in life rendered mutant animals insensitive to monocular deprivation as adults, similar to normal wild-type mice. Short-term presynaptic dynamics reflected a synaptic reorganization in GAD65 knockout mice after chronic diazepam treatment. A threshold level of inhibition within the visual cortex may thus trigger, once in life, an experience-dependent critical period for circuit consolidation, which may otherwise lie dormant.

An extensive series of studies, beginning with the pioneering experiments of Wiesel and Hubel, have shown that correct visual experience is crucial for the development of the visual system. Several years ago, we put forward the hypothesis that neurotrophic factors of the neurotrophin family (NGF, BDNF, NT-3, NT-4) have a role in mediating the effects of visual experience in the developing visual system. This theory is based on the following experimental results: (a) exogenous supply of neurotrophins during the critical period prevents the effects of monocular deprivation; and (b) transplant of cells releasing NGF allows a normal development of the functional properties of visual cortical neurons in dark-reared rats.

Much of what is known about activity-dependent plasticity comes from studies of the primary visual cortex and its inputs in higher mammals, but the molecular bases remain largely unknown. Similar functional plasticity takes place during a critical period in the visual cortex of the mouse, an animal in which genetic experiments can readily be performed to investigate the underlying molecular and cellular events. The experiments of this paper were directed toward understanding whether anatomical changes accompany functional plasticity in the developing visual cortex of the mouse, as they do in higher mammals. In normal mice, transneuronal label after an eye injection clearly delineated the monocular and binocular zones of area 17. Intrinsic signal optical imaging also showed monocular and binocular zones of area 17 but revealed no finer organization of ocular dominance or orientation selectivity. In normal animals, single geniculocortical afferents serving the contralateral eye showed great heterogeneity and no clustering consistent with the presence of ocular dominance patches. Growth and elaboration of terminal arbor continues beyond postnatal day 40 (P40), after the peak of the critical period. After prolonged monocular deprivation (MD) from P20 to P60, transneuronal labeling showed that the projection serving the ipsilateral eye was severely affected, whereas the effect on the contralateral eye's pathway was inconsistent. Optical imaging also showed profound effects of deprivation, particularly in the ipsilateral pathway, and microelectrode studies confirmed continued functional plasticity past P40. Reconstruction of single afferents showed that MD from P20 to P40 promoted the growth of the open eye's geniculocortical connections without causing the closed eye's contralateral projection to shrink, whereas MD from P20 to P60 caused an arrest of growth of deprived arbors. Our findings reveal numerous similarities between mouse and higher mammals in development and plasticity, along with some differences. We discuss the factors that may be responsible for these differences.

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.