Synaptic connections need nurturing to retain their structure and keep outsiders

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Synaptic connections need nurturing to retain their structure and

keep outsiders at bay

http://www.medicalnewstoday.com/medicalnews.php?newsid=33723

The role of Cbln1 offers a new vision for how the adult brain retains

its correct circuitry and how lack of such proteins might contribute

to nervous system diseases.

The ability of the brain to transmit and process information requires

a lifelong commitment to maintaining the integrity of synapses--the

special connections that permit the passage of nerve impulses from

one nerve cell to another, according to investigators at St. Jude

Children's Research Hospital and colleagues in Hokkaido University

School of Medicine (Japan). A report on this work appears in the

November 15 issue of Nature Neuroscience.

This long-term commitment requires proteins called synaptotrophins,

the prototype of which is Cbln1, to maintain countless millions of

synapses in good working order, the researchers said. In the absence

of such proteins, the synapses weaken and eventually fall apart. This

not only compromises nerve transmission, but also provides the

opportunity for other nerves to extend their axons toward these

faltering synapses and make inappropriate connections that further

disrupt brain function.

" Traditionally, studies in this field emphasized the development of

the nervous system, and focused on how axons navigate to the correct

part of the brain and then recognize and make specific synaptic

contacts with the correct type of nerve cells, " said I. ,

Ph.D., a member and co-chair of the Department of Developmental

Neurobiology at St. Jude. " It now appears that there are other

processes at work throughout adult life that maintain the integrity

and function of these connections once they have formed. "

The idea that synapses require maintenance factors in the adult is

not new, although the identification of specific substances that

contribute to this process has proven elusive, said.

Therefore, the researchers used a laboratory model of the cerebellum

to identify proteins that maintain a specific set of synaptic

connections. Using this model they found that Cbln1 maintains correct

synaptic connections after they have been established.

The St. Jude team showed that Cbln1 maintains the connection between

two types of nerves--Purkinje cells and granule cells. Purkinje cells

are large nerves that are aligned like dominos across the upper part

of the cerebellum and send information to other parts of the brain.

Parallel fibers are the axons of granule cells and they form synapses

with the dendrites of Purkinje cells. The investigators showed that

granule cells release Cbln1 from the ends of their axons--the

parallel fibers--in order to maintain their synaptic connections with

these dendrites. Dendrites are threadlike branches on nerves that

conduct incoming impulses from synapses to the body of the nerve

cell.

When the investigators studied the electrical activity at the synapse

between granule and Purkinje cells in models that lacked the gene for

cbln1 (cbln1-/-), they found that the signals in Purkinje cells

stimulated by granule cells were consistently smaller than normal. In

addition, the number of synapses between parallel fibers and Purkinje

cells in cbln1-/- models was markedly reduced compared to cbln+/+

models. This was because the endings of the axons from granule cells

(the presynapse) progressively detached from Purkinje cells. However,

the specialized regions of Purkinje cell dendrites that participate

in the synapse (postsynaptic spines), were still present in normal

numbers. But these unoccupied spines led to a second synaptic

abnormality in the cbln1-/- model: the pattern of synapses between

the Purkinje cells and another type of nerve, called the climbing

fibers, was abnormal. Normally, only one climbing fiber makes a

synapse with a particular Purkinje cell. But in the cbln1-/- models

many climbing fibers had grown into the area of the cerebellum where

Purkinje cells normally form these single synapses with parallel

fibers; and these climbing fibers had established many synaptic

contacts on each Purkinje cell at sites previously occupied by

parallel fibers.

" Nerves are territorial and respond to signals that keep other types

of nerves out of their area of the brain unless they have legitimate

business there, " said. " Without proteins like Cbln1 in the

brain, some nerves extend their axons into neighboring territories,

usurping abandoned postsynaptic sites and disrupting normal

function. "

The researchers also found that Cbnl1 plays a critical role in

maintaining the molecular mechanisms that underlie long-term

depression (LTD) at the parallel fiber-Purkinje cell synapse. LTD, an

experience-dependent modification in the response of a nerve to

stimulation, is viewed as a molecular form of memory. The molecular

machinery that produces LTD is thought to be located in Purkinje

cells. This suggests that Cbln1 released by granule cells must

somehow influence LTD in Purkinje cells, said. The authors

propose this occurs through a protein in the postsynaptic spine

(dendrites) of Purkinje cells called the orphan delta-2 glutamate

receptor. They note that models that lack delta-2 glutamate receptor

in Purkinje cells are nearly identical to models that lack Cbln1 in

granule cells. This suggests that delta-2 glutamate receptor somehow

mediates the action of secreted Cbln1. As both delta-2 glutamate

receptor and Cbln1 are members of larger families of proteins that

have distinct patterns of expression throughout the brain, this type

of interaction might provide a way to ensure that the correct

synaptic contacts form between different sets of nerve cells.

" Our findings are a significant step in our goal of understanding how

the brain maintains its synaptic integrity, " said. " Moreover,

these findings open the possibility that disruption of synaptotrophin

function could play a role in the development of neurological and

psychiatric disorders. Therefore, these proteins and the pathways

through which they function might represent potential targets for

therapeutic intervention in neurological and psychiatric diseases. "

Other authors of the paper include Hirokazu Hirai (currently at Japan

Science and Technology Agency, Kanazawa), Zhen Pang (currently at

Roche Palo Alto, Palo Alto, Calif.), Dashi Bao, Leyi Li,

Parris, and Yongqi Rong (St. Jude); Taisuke Miyazaki, o Miura,

and Masahiko Watanabe (Hokkaido University School of Medicine,

Sapporo, Japan) and Michisuke Yuzaki (currently at Keio University

School of Medicine, Tokyo, Japan).

This work was supported in part by the National Institutes of Health,

the Toray Science and Technology Grant, Japanese Grants-in-aid for

Scientific Research, a Cancer Center Support Core Grant and ALSAC.