Neurobiologists identify widely used assembling and stabilizing forces
behind brain synapses
Neurological pathway shown for the first time to control the flow of
synaptic transmission

Date:
October 6, 2021
Source:
University of California - San Diego
Summary:
Scientists provide promising new evidence that the 'planar cell
polarity,' a powerful signaling pathway, is a widely used mechanism
for the formation and maintenance of a large number of synapses.



FULL STORY ========================================================================== Within the brain and other parts of the nervous system, synapses are key junctional points in between neurons (the nerve cells) where critical
signals are transmitted. More specifically, the "glutamatergic" synapses
are the prime "excitatory" synapse junctions that neurons use to activate
each other and are known to have broad diversity in size and shape.


==========================================================================
A longstanding missing piece of the synapse puzzle has been an explanation
for how glutamatergic synapses are assembled and maintained, leading
to further questions about whether a common development mechanism, or
pathway, even exists for the large numbers and many types of glutamatergic synapses.

Scientists at the University of California San Diego have been piecing
together the mechanisms that appear to plug this gap in neurobiological knowledge.

Postdoctoral Scholar Yue Ban, Professor Yimin Zou and their colleagues
provide promising new evidence Oct. 6 in the journal Science Advances
that the "planar cell polarity," or PCP, a powerful signaling pathway
that systematically polarizes cells and tissues along the plane of the
tissues, is a widely used mechanism for the formation and maintenance
of a large number of synapses.

"One main conclusion of this paper is that the planar cell polarity
pathway is responsible for the formation and maintenance of a very
large majority of glutamatergic synapses," said Zou. "Building on a
previous study where we initially showed the function of the members of
the PCP signaling pathway in synapse formation, this new paper further highlights the significance of this pathway in controlling synapse
numbers in both the developing and mature brain." In the new study, the
Zou lab focused on the role of a key PCP component called Prickle, which
in mice features four family members. After Prickle1 and Prickle2 were specifically knocked out in the hippocampus and the prefrontal cortex,
the researchers found a 70-80% reduction in the number of glutamatergic synapses. When these genes were deleted in early development, 70-80% of
the synapses failed to form. When these genes were deleted in adulthood,
70-80% of the synapses disappeared.



==========================================================================
To further explore how Prickle regulates synapse numbers, the Zou lab
generated mice that mimic a human mutation of Prickle2, which is known
to cause autism.

These mice showed a reduction or delay in synapse formation and a
high reduction in the amount of key proteins in the synapses, such as
the glutamate receptors, which are ion channels that detect glutamate
released from the presynaptic neurons to activate the postsynaptic
neurons. These results suggest that some of the mutations of Prickle2 may render the mutant Prickle2 protein less efficient in assembling synapses
or recruiting key proteins essential for the function of synapses. These mutations provide valuable inroads to further dissect the mechanisms of
synapse formation and maintenance.

Also in this study, the researchers discovered that Prickle2 promotes
synapse formation and acts as a stabilizing force for the key protein
complex formed by the PCP proteins that bring the two neurons together
at the synapses. A mutant Prickle protein was not able to stabilize this protein complex.

"Another main conclusion of this research is that the stability of the intercellular complex of PCP proteins, which we have recently found
critical for synapse formation and maintenance, is promoted by Prickle,"
said Zou.

"Knowing how the PCP complex regulates synapse formation and maintenance
paves the way to understanding many important biological and pathological processes that involve changes in synapse numbers. For example, Prickle's function maybe comprised in pathological conditions, which can lead to the instability of synapses in neurodegenerative disorders or other diseases."
"We have previously found that another PCP protein, called Vangl2,
destabilizes synapses," said Zou. "Here we show that Prickle antagonizes
Vangl2 with a mechanism which we are still trying to discover. Therefore,
our synapses are constantly under the control of the stabilizing and destabilizing forces and this is part of the reason that our brain, or
at least part of it, undergoes constant changes." (See attached figure
adapted from Yue et al, Science Advances, 2021).

Zou and his colleagues now believe this intercellular complex of PCP
proteins is intrinsically asymmetric and provides the key directional
signal to polarize cell-cell junctions. This is how PCP signaling
introduces cell and tissue polarity. The researchers in the Zou lab
obtained evidence that the asymmetry of this complex bridging the
two neurons may lead to the asymmetric assembly of presynaptic and
postsynaptic complexes across the synapse and ultimately determines
the direction of the flow of neural signals, a fundamental feature of
neuronal synapses.

"This is the first time that a pathway controlling the direction of
synaptic structures and synaptic transmission has been identified,"
said Zou.

Yue Ban, Ting Yu, Bo Feng, Charlotte Lorenz, Xiaojia Wang, Clayton
Baker and Yimin Zou are the authors of the Science Advances study. The
project was supported by grants from the National Institutes of Health
(RO1 MH116667 and R21 NS111648) to Yimin Zou.

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Mario
Aguilera. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yue Ban, Ting YuBo Feng, Charlotte Lorenz, Xiaojia Wang, Clayton
Bakerand, Yimin Zou. Prickle promotes the formation and maintenance
of glutamatergic synapses by stabilizing the intercellular
planar cell polarity complex. Science Advances, 2021 DOI:
10.1126/sciadv.abh2974 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211006143442.htm

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