NCBS: Zebrafish study reveals how the brain makes its connections

How nerve-end connections known as synapses form is highlighted in this study of Purkinje neurons in the cerebellum of knockout zebrafish

January 08, 2022 08:08 pm | Updated January 09, 2022 08:16 pm IST

Transparent fish:  Neuron development in zebrafish can be observed by injecting a dye or engineering the fish to express fluorescent proteins.

Transparent fish: Neuron development in zebrafish can be observed by injecting a dye or engineering the fish to express fluorescent proteins.

Neurons, or nerve cells, in the brain connect by means of junctions known as synapses through which they transmit signals. Recent work by researchers at the National Centre of Biological Sciences, Bengaluru, has thrown light on what stimulates these synapses to form.

There are two types of synapses – chemical and electrical. In chemical synapses, there is a space of about 20 nanometres between two neurons, and the way they communicate is this: One neuron converts electrical signal into chemical signals and this chemical is released into the synaptic space and the receiving neuron converts the chemical signal back into an electrical signal.

As far as the electrical synapse goes, this is not the way it operates. In these synapses, the two neurons have a physical connection and the conversion of electrical to chemical need not occur, and they communicate directly. Electrical synapses are like a physical wire, communication is faster but they are also fewer in number.

Neuron handshake

It was shown that electrical synapses are formed before chemical synapses, they are like a blueprint in which neurons make a handshake. This results in the making of chemical synapses. Research on organisms such as leeches showed that if you remove electrical synapses, the chemical synapses do not form. However, the mechanism of how it happens in higher organisms such as vertebrates was not known.

Researchers from TIFR-National Centre of Biological Sciences, Bengaluru, have chosen Zebrafish as a model organism to study this process. Zebrafish are transparent and neuron development in larval zebrafish can be observed from day to day by injecting a dye or by engineering the fish to express fluorescent proteins.

Purkinje neurons

The group observed that knocking out a particular protein known as the gap junction delta 2b (gjd2b) in the cerebellum of zebrafish affected levels of an enzyme CaMKII. Levels of CaMKII were seen to increase in the Purkinje neurons in the cerebellum. These neurons and the cerebellum itself control co-ordination of movements in the organism. In humans for example, excess abuse of alcohol leads to damage of these cells, which results in lack of co-ordination in movement.

As Prof. Thirumalai explains, the cerebellum shows an evolutionary continuity in all vertebrates, so, too, the Purkinje neurons. Even though fish and humans diverged from a common ancestor about 500 million years ago, the cerebellum has been evolutionarily conserved. While zebrafish have about 300-400 Purkinje neurons, humans have thousands of these.

Dendrite arbours

“Normally, levels of CaMKII are low in developing (immature) neurons and high in mature neurons, and the increased level actually freezes the development of dendrite arbours,” says Vatsala Thirumalai of NCBS, who led the work published in eLife. Dendrite arbours are branched ends of neurons, given this name because of their tree-like structure. “In the absence of gap junction protein, CaMKII levels prematurely increase, preventing arbours from forming. Thus, chemical synapses do not form.”

The work uses advanced techniques such as time-lapse microscopy and confocal microscopy which allowed the group to observe how the neuronal cells grow in the fish brain day after day. Electron microscopy was used to view slices of the brain to count the number of synapses present.

To make the mutant fish with gjd2b protein knocked out, the group used the genome editing tool TALEN (Transcription Activator-Like Effector Nuclease). “It is possible to do such exciting research using the latest and most advanced tools and techniques in India today. I hope this trend will encourage more students to take up a career in research,” says Prof. Thirumalai.

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