Study shows how astrocytes regulate formation of synapses in neurodevelopment.


During brain development, the formation of neuronal synapses at the right time, in the right place, and of the right strength is crucial to the ongoing function of the brain throughout life.  However, just how that happens, and which molecular signals are involved is still not fully understand.  Now, a study from researchers at the Salk Institute shows that brain cells called astrocytes initiate communication between pairs of neurons early in neurodevelopment by inducing specific changes in both members of the pair. The team state that their work has important implications for neurodevelopmental disorders such as autism, ADHD and schizophrenia that are thought to result at least partly from faulty communication between neurons.  The opensource study is published in the journal Neuron.

Previous studies show that astrocytes are necessary for neurons to form synapses with recent studies from the lab showing that a protein secreted by astrocytes named glypican 4 induced communication between nearby neurons. With glypican 4 present, presynaptic neurons sending information partner effectively with postsynaptic neurons receiving it.  However, the exact mechanism behind this process is unknown.  The current study investigates the molecular mechanism of how glypican 4 exerts its effect.

The current study treats cultures of neurons with either glypican 4 or another astrocyte-secreted protein called thrombospondin, which induces changes in neurons and doesn’t result in any synaptic communication.   Results show that 49 genes are activated in response to treatment with glypican 4, and 3 genes are activated in response to thrombospondin. The lab explain the fact that there is no overlap between the genes suggests that the two proteins are involved in very different cellular systems, and that glypican 4 is critical to making synapses active.

Results show that glypican 4 increases the numbers of specific kinds of receptors on the receiving postsynaptic neurons. Data findings show that glypican 4 recruits receptors to the cell surface by inducing the release of a protein called neuronal pentraxin 1 (NP1) which directly binds to the receptors. The group state that without NP1 binding to the receptors synapses remain silent meaning that glypican 4 is needed to make postsynaptic neurons receptive to input.  They conclude that presynaptic neurons release NP1 specifically in response to glypican 4, meaning that a single protein released by astrocytes is responsible for enabling meaningful connections by acting on both sending and receiving neurons.

The team surmise their data identifies a signaling pathway which regulates synaptic activity during central nervous system development, and demonstrates a role for astrocytes as organizers of active synaptic connections by coordinating both pre- & post synaptic neurons. They go on to add that as mutations in glypicans are associated with neurological disorders, such as autism and schizophrenia, this signaling cascade offers new avenues to modulate synaptic function in disease.  For the future, the researchers state that their work will explore ways of targeting astrocytes to come up with novel therapies for neurological disorders.

Source: Salk Institute for Biological Studies

 

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