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Genetic ‘GPS’ System Created To Comprehensively Locate And Track Inhibitory Nerve Cells

A team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has succeeded
in creating what amounts to a GPS system for locating and tracking a vital class
of brain cells that until now has eluded comprehensive identification,
particularly in living animals.

The cells in question are the class of
neurons that release the neurotransmitter called GABA (gamma aminobutyric acid).
GABA neurons function to inhibit or dial down the intensity of nerve signals
propagated by excitatory neurons, which are triggered by neurotransmitters such
as glutamate.

Excitatory neurons account for about 80% of all the
neurons in the mammalian cortex. But without the modulatory intervention of the
much rarer GABA neurons within the circuits they form, normal brain function
would be impossible. Uninhibited neuronal excitation would lead to a constant
state of seizure something like what is seen, episodically, in epilepsy.

Neuroanatomists have been trying
to map the brain’s circuitry for well over a century, but the organ’s
astonishing complexity – anatomical and functional – has insured that progress
has been slow. Researchers have been able to map the entire set of circuits in
the roundworm C. elegans. But that humble creature has only 302 neurons.
The brains of mammals have millions of neurons, and within the tangle formed by
their projections, called axons and dendrites, one finds those vital GABA cells,
which until now could not be identified in any consistent way globally,
throughout the mammalian brain.

CSHL Professor Z. Josh Huang and
colleagues in his neuroscience lab have spent portions of the last five years
working on a project to comprehensively label GABA neurons. The results of their
highly time-consuming labors are described in a paper appearing Sept. 22 in the
journal Neuron. The paper is likely to be influential in the neuroscience
community since it describes the creation of different lines of mice expressing
genetic triggers that enable GABA neurons to be identified very specifically, by
subtype, and to be tracked and manipulated in real time in living animals.

A multi-faceted toolkit for all scientists to use

Called
“Cre driver lines,” Dr. Huang’s approach makes use of a well-established and
widely used technique called Cre-Lox recombination to create the equivalent of
genetic handles in specific types of cells within the cerebral cortex. Different
strains of mice have been developed, each to express a particular gene or genes
that enable microscopists to home in on particular subtypes of GABA neurons. The
key, Huang explains “is that the ‘driver’ in each case is a gene that we know
something about. We know its expression correlates with a subset of GABA
neurons. We use that gene as a kind of entry point to express various kinds of
markers.”

The current paper describes 20 mouse lines that have been
engineered in various ways. These can be used to activate molecular “reporters”
that label different GABA cell types, or to make the targeted cells responsive
to beams of colored laser light – a technique called optogenetics. They also
enable researchers to follow axonal paths that connect particular GABA cells
with other cells by incorporating deactivated retroviruses. “Optogenetics and
retroviral labeling are wonderful techniques, but they are not, by themselves,
cell-type specific. We’ve built a system that integrates all of these
technologies, which can now be mobilized with exquisite specificity,” Huang
says.

The net result is a toolkit – which will grow to include more
mouse lines – for the use of experimentalists in labs everywhere, and which
enables comprehensive and systematic exploration of inhibitory GABA neurons.
Perhaps most exiting to Huang is the opportunity to view the manner in which
inhibition functions in a living brain.

“The functional circuit, even
though it is so complex, is in a sense being configured every second, every
minute that we live, and on a massive scale within the brain. It has to be
incredibly dynamic, responding to incoming inputs continuously. As this
information is coming in, the circuit is adjusting within a time scale on the
order of tens of milliseconds.

“You can think of the inhibitory
modulation as a system of control for ensembles of neurons, both in spatial and
temporal terms. It’s a system that must depend upon a very stringent genetic
program – we can assume this is true since the outcome is almost always right.
But we also know how important the proper ‘tuning’ must be, based on our
observations of neuropsychiatric and other brain illnesses. If the system is not
in balance, you can have major illnesses such as schizophrenia or
autism or epilepsy.”

Early discoveries

While the main purpose of the work just
published was to create a resource for neuroscientists, the Huang lab’s first
experiments with newly engineered mouse lines have enabled them to see things
never before seen. In one experiment, the CSHL team has been able to track the
migration of GABA neurons from the site of their “birth” in a structure called
the MGE (medial ganglionic eminence), along a route that takes them to specific
spots within the cortex. “It’s fascinating,” says Huang. “They are generated far
outside the cortex – to make an analogy, it’s as if they were born in Africa and
take various but very specific routes to another continent. Once you track them,
as we have, you can see these paths are not random; they are like highways.”

More generally, says Huang, “Not only can we now watch specific
inhibitory cell types from early in development; we can also watch as they
migrate and establish connections, grow dendrites, make synapses. I would argue
this ‘Gene-based cell Positioning System’ is even better than GPS, because it
allows us to track how the circuits actually assemble.”

This research
was supported by grants from the National Institutes of Health. Participating
scientists were sustained in part by a NARSAD postdoctoral fellowship, a
McKnight Fellowship and a Simons Investigator award.

Source: MedicalNewsToday.com

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