August 27, 2009 -- In a new study, researchers at the Montreal Neurological Institute and
Hospital (The Neuro), McGill University have found an important
mechanism involved in setting up the vast communications network of
connections in the brain.
A signaling pathway involving
interactions between a schizophrenia-linked gene product, Calcineurin,
and a transcription factor known as Nuclear Factor in Activated T-cells
(NFAT) contributes to the connectivity at nerve cell (neuron) junctions
or synapses and affects the extent of nerve cell projections or
dendritic branches, in the visual system. The results of this study,
published in the journal Neuron, may bring hope to adults suffering
from brain injuries and offer the possibility of early diagnosis,
treatments and therapies for schizophrenia, autism or other
developmental disorders where abnormal neurological wiring is thought
to occur early in life.
In early brain development, there is an overabundance of unspecified
connections between neurons. During development (and learning), these
connections are pruned, leaving the stronger and more specific ones.
This refinement occurs in response to a set of inputs from the
environment, and is traditionally thought to be mediated through
changes at synapses - the specialized junctions through which neurons
communicate with each other.
Neurons possess an innate
tendency to extend branched projections from the cell body known as
dendrites. Dendrites receive information and form synaptic contacts
with the terminals of other nerve cells to allow nerve impulses to be
transmitted. In the so-called "synaptotropic model" of dendritic
development, interactions between dendrites and potential synaptic
partners provide the extrinsic cues that help direct dendritic growth
into patterns that optimize synaptic interactions. Therefore, growth or
branching is most likely to occur in regions where there is a
stabilized synapse and retraction is more likely in regions where
synapses fail to mature or become destabilized.
"Our study shows
that changes in synaptic connections are also controlled by alterations
in the transcriptional profile of the cell which governs protein
production," says Dr. Edward Ruthazer, neuroscientist at The Neuro and
lead investigator of the study. There is a growing body of evidence
that transcriptional regulation, an important step in the process of
making proteins, is a key regulator of long-term changes in synaptic
The protein Calcineurin (CaN) regulates
transcriptional programs that control synapse formation and function.
It has also has been strongly implicated in weakening connections
between cells, and is a likely regulator of pruning of connectivity.
CaN instructs the neurons through the transcription factor NFAT, which
in turn plays an important role in axonal outgrowth and neuronal
response to extrinsic cues involved in circuit development and
Neil Schwartz, a graduate student in Dr. Ruthazer's
lab designed a method of specifically blocking the interaction between
CaN and NFAT at the nucleus in order to examine the effects on neuronal
connections in the visual system. "We found that inhibiting the
function of CaN resulted in more dendritic branches and more synapses,
demonstrating that CaN is a potent regulator of dendritic complexity
and synaptic function," explained Dr. Ruthazer. "We further
demonstrated that CaN mediates its effects on neurocircuitry through
its activation of NFAT transcription factors and that NFAT activity in
the developing brain can be regulated by natural visual stimulation.
extension of the synaptotrophic model taking into consideration not
only the interactions with synaptic partners that shape the neural
architecture, but also the transcriptional profile of nerve cells,
provides vital insight into diseases in which there is abnormal neural
connectivity and offers the possibility of early diagnosis and
Source : Montreal Neurological Institute and Hospital