Neural networks formation
The main function of the brain is to plan and execute rapid responses to changes in the environment. But how does the brain become such an extraordinary tool for information processing? During development, undifferentiated progenitor cells are assembled into sophisticated neural networks with precise patterns of connectivity. This process is guided by a causal chain of formative events. First, endogenous spontaneous oscillations drive a phase of exuberant growth of dendrites and synapses: a coarse network is formed. Then GABA switches polarity and the network is gradually refined. This is a critical period, because changes in the timing or sequence of these events have catastrophic effects later in life (Figure 1).
Figure 1. A critical period in neural network development occurs in the first few weeks of postnatal life in rodents. The majority of synaptic connections are formed during this period. A first phase of rapid growth is sustained by mature synchronous neuronal activity, due to the fact that GABA is also depolarizing at this stage. Then GABA becomes hyperpolarizing like in the adult and the network transitions to a phase of consolidation and refinement. We are interested in the mechanisms that maintain the correct developmental trajectory.
Despite an increasingly clear picture of the role and importance of these formative events, our understanding of the molecular programs that instruct them is very poor. The reason for this gap in knowledge is simple: it is an almost intractable problem. Two thirds of all transcriptional changes occur between the embryo and early postnatal (PN) life (Figure 2). How do we find the key molecular players among this staggering number of genes?
Figure 2. Multidimensional scaling (MDS) plot of transcriptional differences in the human central nervous system across time. Each dot is the transcriptome from a brain sample. Dots that cluster close to each other have similar patterns of gene expression. Dots that are far apart are the most dissimilar. Notice that The most pronounced differences (approximately two thirds) occur during prenatal development. By contrast, over four decades of adulthood, less than 1% of genes are differentially expressed. Adapted from Silbereis, Neuron, 2016.
The goal of the Lippi lab is to use miRNAs to reveal the molecular logic driving network formation. miRs are a very interesting class of ncRNAs. miRs are master regulators of gene expression: a single miR can target hundreds of different mRNAs, orchestrating fast and flexible repression of convergent gene programs. We were the first to show that a specific miR, miR-101, is necessary during the critical period that instructs network assembly (Lippi, Neuron 2016). Inhibition of miR-101 causes excessive network excitability and cognitive impairments, core clinical manifestations of many neurodevelopmental disorders, such as epilepsy, autism, and schizophrenia. Identifying miR-101 targets revealed a restricted set of highly interconnected gene programs that drive the development of the excitatory input. Interestingly, many of these genes had already been causally linked to neurodevelopmental disorders.
We intend to use miRs to address fundamental questions about network development, to make sense of the complex regulatory gene programs underlying it, and to identify potential nodes of vulnerability to disease.
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