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The Switch

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Learning and memory are regulated by the hippocampus of the brain. Scientists have now found the molecule that decides how many neurons the hippocampus will have.


Shubha Tole couldn’t have asked for a better birthday present. Two doctoral students in the lab of the neurobiologist — who will turn 44 later this month — at the Tata Institute of Fundamental Research (TIFR) in Mumbai have unravelled a mechanism that has puzzled brain researchers for years. Anindita Sarkar and Lakshmi Subramanian have found the substance that gives the brain the signal to stop producing neurons and start forming glia cells.

Neurons are the brain cells that transmit information. Glia cells, which are far more numerous in the brain, supply nutrients to neurons and protect them from toxic attacks as well as maintain glucose levels in the brain.

The scientists studied the hippocampus — the region where learning happens and memories are formed — and found that a gene called Lhx2 has a critical role in deciding the number of neurons and glia cells. Interestingly, both types of cells are formed from the same stem cells. Scientists have known for a while that in a developing brain (in the embryo stage) the production of glia cells — particularly star-shaped astroglia cells that surround neurons to insulate and support them — commences only after the production of neurons stop. But they didn’t know what drives this switch.
Learning and memory are regulated by the hippocampus of the brain. Scientists have now found the molecule that decides how many neurons the hippocampus will have. T.V. Jayan reports

The findings, announced in a recent issue of the Proceedings of National Academy of Sciences journal, not only contribute significantly to the understanding of brain formation but also have clinical implications. It may help doctors understand the mechanisms underlying disorders like temporal lobe epilepsy (TLE) better, hopefully leading to better clinical intervention.

The TIFR scientists found that when they inactivated the Lhx2 gene in mice embryos, the production of neurons in the hippocampus stopped, triggering an early onset of astroglia production. And when the gene was kept active longer than normal, neuron production too continued longer than usual.

“Our experiment has clearly demonstrated that the levels of Lhx2 decide the fate (of brain stem cells),” Tole told KnowHow. “It decides whether the glia-making pathway can be allowed to work or not.”

“This indicates the presence of a molecular timer that brings about the switch from neuron-making to glia-making,” says Aurnab Ghose, a neurobiologist at the Indian Institute of Science Education and Research (IISER) in Pune. This is an important step in understanding the regulation of timing in brain development.

According to Tole, striking the right balance between neurons and astroglia is critical. “If there are not enough neurons in the hippocampus, its function will be compromised,” the TIFR scientist says.

The mismatch between neurons and astroglia cells is implicated in TLE. “Loss of neuronal population (atrophy) and proliferation of astroglia in the hippocampus is the commonest pathology encountered in patients with drug-resistant TLE,” says K. Radhakrishnan, neurosurgeon and director of the Sri Chitra Tirunal Institute of Medical Sciences and Technology (SCTIMST) in Thiruvananthapuram. This means that TLE patients have too many glia cells in their hippocampus and keep losing neurons.

Such loss of neurons is found in nearly two-thirds of TLE patients. Though it was first described more than a century ago, it is not yet clear how this happens, says Radhakrishnan. It is presumed that febrile seizures occurring at a vulnerable period in early childhood in a person with a differently developed hippocampus results in the loss of neurons (hippocampus sclerosis).

The research provides an important insight into the factors that control the development of the hippocampus and at least one of the mechanisms that result in a differently developed hippocampus, the SCTIMST director says.

“How this information translates into human hippocampus sclerosis shall remain elusive till we learn more about the molecular genetic association of Lhx2 function/dysfunction in people with TLE,” says Radhakrishnan.

Significantly, switching on glia production in the hippocampus is not the only thing that Lhx2 does. Nearly three years ago Tole’s team, working jointly with their US counterparts, found that Lhx2 nudges brain stem cells to turn into the cerebral cortex. The cerebral cortex, which consists of the hippocampus and the neocortex, is involved in higher functions like language and complex thinking, apart from memory formation.

Interestingly, the TIFR scientists found that Lhx2 has no hold over the process of switching from neuron making to glia making in the neocortex. “We think that some other molecule may be doing that job,” says Tole.

“Lhx2 was already known to have a fundamental role in early brain development, required for the cortex to form in the first place instead of non-cortical structures. The current study uncovers an additional later role in development that is equally fundamental,” says Tole.

It is surprising that the same molecule has two really powerful roles to play. “It looks like a good example of evolutionary parsimony (one molecule having more than one critical function),” says Ghose.

Here’s to multitasking, Nature’s way!

Source : The telegraph ( Kolkata, India)

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