Susan Birren, Ph.D.
Associate Professor of Biology
Volen National Center for Complex Systems
Brandeis University
Waltham, Massachusetts
From Heart to Brain: Controlling
Neuron Development and Function
Cardiac function is modulated by norepinephrine release
from innervating sympathetic neurons. These neurons also
form excitatory connections onto cardiac myocytes in culture.
Dr. Birren’s lab has shown that the neurotransmitter properties
of these target connections are modulated by target-derived
neurotrophic factors. Nerve growth factor (NGF) increases
the activity- dependent release of norepinephrine from
sympathetic synapses, acutely potentiating excitatory
transmission. In contrast, brain-derived neurotrophic
factor (BDNF) regulates the release of a second neurotransmitter,
acetylcholine, leading to a rapid shift to inhibitory
cholinergic transmission in response to neuronal stimulation.
These data indicate that sympathetic control of cardiac
function can be rapidly modulated by the availability
of specific factors from the target. The actions of BDNF
are mediated through the p75 neurotrophin receptor. P75-/-
neurons do not release acetylcholine in response to BDNF,
while neurons overexpressing p75 show increased cholinergic
transmission. These results demonstrate a novel role for
p75 in modulating the release of distinct neurotransmitter
pools, resulting in a functional switch between excitatory
and inhibitory neurotransmission in individual neurons.
The p75 receptor also regulates neurotransmitter properties
in the central nervous system. Interactions between GABAergic
and cholinergic neurons define the output of basal forebrain
projections and thus contribute to the development and
functional properties of cortical circuits. They have
shown that the p75 receptor influences the relative number
of basal forebrain cholinergic and GABAergic neurons.
In the absence of p75, GABAergic neurons develop, but
GABAergic development is no longer affected by neurotrophins.
Since p75 is not actually expressed in the GABAergic population,
this defines a new, non-cell autonomous mechanism of p75
action. Neighboring cholinergic neurons do express p75
and they have demonstrated that neurotrophin activation
of cholinergic p75 results in release of a soluble factor
that modifies neurotrophin responses of nearby neurons.
Thus, p75-mediated interactions between cholinergic and
GABAergic neurons, together with activity-dependent responses,
regulate the balance of excitatory and inhibitory components
of basal forebrain circuits.
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