The APCs of nerve cell function

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The APCs of nerve cell function

http://www.eurekalert.org/pub_releases/2008-06/tuhs-tao061608.php

Rapid information processing in the nervous system requires synapses,

specialized contact sites between nerve cells and their targets. One

particular synapse type, cholinergic, uses the chemical transmitter

acetylcholine to communicate between nerve cells. Cholinergic

synapses are essential for normal learning and memory, arousal,

attention, and all autonomic (involuntary) nervous system functions.

Malfunction of cholinergic synapses is implicated in Alzheimer's

disease, age-related hearing loss, autonomic neuropathies, and

certain forms of epilepsy and schizophrenia. Despite the importance

of cholinergic synapses for cognitive and autonomic functions, little

is known about the mechanisms that direct their assembly during

development. In a new study published in the June 2008 issue of

Molecular and Cellular Neuroscience, researchers at Tufts University

School of Medicine (TUSM), uncover mechanisms that direct cholinergic

synapse assembly between neurons in vivo.

" We have identified the protein adenomatous polyposis coli (APC) as a

key organizer of a multi-protein complex that is required for

assembly of neuronal cholinergic synapses " says corresponding author

Michele H. , PhD, professor of neuroscience at TUSM and member

of the neuroscience program faculty of the Sackler School of Graduate

Biomedical Sciences. " APC is expressed in all cell types and has

multiple functions and binding partners. It is best known for its

role in colorectal cancer. Our work defines a novel role for APC in

neurons. We show that APC brings together several proteins at the

synapse and coordinates their functions in directing the surface

membrane delivery and stable retention of nicotinic acetylcholine

receptors at the synapse. "

" A single nerve cell synthesizes multiple different neurotransmitter

receptor types. The nerve cell must target each of them to distinct

synaptic sites that oppose incoming nerve cell contacts that release

the correct transmitter to activate that receptor type. Matching of

receptor and transmitter types is critical for proper function, "

states Madelaine Rosenberg, PhD, first author and research associate

in the department of neuroscience at TUSM. Rosenberg says that APC

and its associated proteins play a key role in accomplishing this

task at cholinergic synapses. The authors report that APC interacts

with and positions the microtubule plus-end binding protein EB1 and

thereby directs the delivery of acetylcholine receptors to restricted

surface membrane regions. APC and EB1 interact with other proteins,

cytoskeletal regulators and adapter proteins, which together

stabilize the scaffold at the synapse and link acetylcholine

receptors to APC at the complex. This study identifies several novel

components of neuronal nicotinic cholinergic synapses.

and colleagues showed that blocking APC function led to

dramatic and specific decreases in acetylcholine receptor levels at

synapses. They showed this by using molecular techniques to

manipulate APC protein interactions during synapse formation. " We

study an in vivo model system to gain insights into mechanisms that

likely direct synapse assembly and function in the human nervous

system, " explains. She further suggests that their

data " support the emerging concept that APC is a central organizer of

a core multi-protein complex that directs the assembly of excitatory,

but not inhibitory, synapses in the vertebrate nervous system. The

importance of APC's neural role is highlighted by reports that loss

of function gene mutations correlate with mental retardation,

schizophrenia, and autism spectrum disorders. " notes, " By

identifying the synapse organizing role of APC and its associated

proteins, our findings bring us closer to understanding disorders of

cognition and neurological function on a molecular level. "

This study is funded by the National Institute of Neurological

Disorders and Stroke (NINDS) through grants to Dr. and the

Tufts Center for Neuroscience Research, and the National Institute of

Diabetes and Digestive and Kidney Diseases (NIDDK) through Tufts

Medical Center Digestive Disease Center. Both NINDS and NIDDK are

part of the National Institutes of Health.