Scientists understand that it takes multiple encounters for mammalian synapses to form long-term partnerships. During development, the potential synaptic partners interact to determine which partners are the best matches. The presynaptic axon and the postsynaptic dendrites must have the right physical chemistry followed by an activity-dependent process which refines and strengthens partners firing in synchrony. The competing partners that fire asynchronously are eliminated. We examined the following: 1) how early axon-dendritic interactions help to find synaptic partners in the right categories, 2) identifying synaptogenic and antisynaptogenic factors that strengthen the appropriate connections, and 3) how neuronal activity controls the expression of genes that shape and coordinate the formation and stability of neuronal circuits. In the review, Dr.Lu et al (Current Opinion in Neurobiology 2009) revealed how early axon-dendritic interactions help to determine long-term synaptic partners. Neural circuits are formed during development and altered by experiences. The assembly of neural circuits is dependent upon regulation of synaptic connectivity by synaptic molecules and neuronal activity. Much focus has been in identifying the synaptic molecules involved in synapse formation. We reviewed data identifying synaptogenic and antisynaptogenic factors that strengthen these connections, and looked at how neuronal activity controls the expression of genes that shape and coordinate the formation and stability of neural circuits. Synaptogenic and antisynaptogenic factors worked synergistically to ensure the timing and specificity of circuit formation, production and maturation. More research is uncovering how neuronal activity manages the balance between excitatory and inhibitory synapses. Distinct factors seem to regulate excitatory and inhibitory synaptic connections. For example, several transcription factors along with activity-regulated gene Brain-Derived Neurotrophic Factor (BDNF) were shown to selectively regulate cortical inhibitory circuits by promoting gamma-aminobutyric acid (GABA) synapse formation. All this information is useful in our current studies. The challenges ahead are: 1) to identify molecular mechanisms underlying the formation of synapses in specific brain regions, 2) bring to light the distinct yet overlapping sets of genes that are regulated under different activity, and 3) to unravel the spatial selectivity and temporal coordination of synapse development in neural circuits. This year our lab produced Activity-Regulated Cytoskeleton-Associated (ARC) -/- (double knockout) mice to be used in a collaborative project studying how the loss of the ARC protein may alter the effects of sensory experience or deprivation in the visual cortex (V1), McCurry et al (Nature Neuroscience 2010). It is suggested that there are many molecular mechanisms involved in experience-dependent changes that occur in the visual cortex during development. The data indicate that the loss of ARC protein leads to an absence of ocular dominance plasticity in response to brief and extended monocular deprivation as well as open-eye potentiation, suggesting that ARC is necessary for deprived-eye depression that normally takes place after monocular deprivation, as seen in the normal mice. The observed deficits occurred in the absence of major changes in visual response properties, since ARC -/- mice exhibited normal visual acuity and retinotopic organization. One precaution to this study is that our mouse germ-line is missing ARC at birth and ARC may affect the normal development of V1 before any experience-dependent activities occur. Protein expression studies have shown that ARC is undetectable before eye opening in V1, but the protein rapidly increases only after eyes open during the period that experience-dependent processes occur. ARC may play a role in the refinement of response properties such as the reduction or removal of weaker inputs and the potentiation of stronger inputs giving rise to sharpened receptive field properties. This study discovered that when the visual cortex is missing the ARC gene, sensory experience or deprivation cannot alter visual cortical functions. Our lab continues to investigate the mechanisms by which experience-induced molecular changes impact on cortical processing of sensory information. We continue to develop molecular genetics tools that would label behaviorally activated neurons in a spatially and temporally controlled manner, therefore facilitating optical tracking of activated neurons and their morphological changes. We continue to develop mouse genetics-based systems to optically activate or silence selected groups of neurons in order to probe their functional contributions to circuit outputs and adaptive behaviors. Our group continues to investigate the coupling mechanisms between sensory stimuli evoked neuronal activity and plasticity-related gene expression in cortical circuits, using calcium-sensitive fluorescent dyes and genetically encoded fluorescent reporters in the ARC gene. Particularly, we are examining whether the induction of activity-dependent gene expression is modified under the direct influence of specific neuromodulators that are associated with the motivational or emotional relevance of a given sensory experience. Finally, we continue applying our opto-genetic systems to study cortical dysfunctions in the mouse models of schizophrenia as developed by the other research groups in the Genes, Cognition and Psychosis Program. In particular, by crossing transgenic mice carrying the risk alleles of candidate genes such as catechol-O-methyltransferase (COMT) and potassium channel (KCNH2) with our optical reporter and actuator lines, we will have the ability to monitor the development of abnormal cortical circuits in real time, and investigate the interactions of genetic risk factors with environmental and social stressors.
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