of the Max - MDC

Neuronal Connectivity
Fritz G. Rathjen
Aneuron establishes thousands of synapses which are the fabric of the communication within the
nervous system. The number, strength as well as specificity of synapses and the balance between
inhibitory and excitatory neurons determines brain function. A longstanding goal of neuroscientists
therefore is to understand how the enormous degree of connectivity of neurons is established
during embryonic and early postnatal development and how this connectivity becomes modulated
by experience-dependent processes. The research of the group focuses currently on two molecular
aspects of neuronal connectivity: formation of axonal branches and regulation of synapse
formation.
cGMP signalling including the receptor guanylyl
cyclase Npr2 and the cGMP-dependent kinase I is
essential for sensory axon branching within the
spinal cord
To establish synaptic contacts, neurons must extend axons
and dendrites which are guided to their target region by the
growth cone which responds to an array of molecular signals.
One principle process that defines the pattern of axonal
trajectories is the formation of axonal branches in specific
regions during the period of outgrowth. It allows axons to
innervate multiple targets and is thus important for the
integration of information from a larger number of primary
neurons. Despite intensive research efforts the molecular
signalling pathways underlying axonal branching remained
poorly understood. We have been therefore interested in
the molecular analysis of axonal branching and studied this
in sensory axons projecting into the spinal cord.
Dorsal root ganglion (DRG) axons enter the spinal cord at
the dorsal root entry zone (DREZ) where they bifurcate into
a rostral and a caudal arm. These arms extend longitudinally
over several segments but remain confined to the oval bundle
of His. Collaterals are then generated from these stem
axons to penetrate the gray matter. Cutaneous sensory collaterals
are confined to the dorsal horn whereas collaterals
of muscle spindle Ia afferents grow to the ventral cord
(scheme in Figure 1A). Thus, from a structural point of view,
sensory axons display at least two types of ramifications
within the cord: (1) bifurcation at the DREZ and (2) interstitial
branching from stem axons to generate collaterals.
Our investigations on this axonal system identified cGMP
signalling by the receptor guanylyl cyclase Npr2 (also
known as GC-B) and the serine/threonine kinase cGKI to be
important for bifurcation at the DREZ (Figure 1B-F). In the
absence of one of these components sensory axons lack the
T-shaped branch, instead the ingrowing axon turns only
rostrally or caudally. In contrast, interstitial branching of
collaterals from the stem axon remains unaffected. The
bifurcation error at the DREZ, in its turn, is accompanied by
a reduced synaptic input received by second order neurons
within the superficial dorsal horn which are the first relay
station of nociceptive sensory axons.
Regulation of synapse formation by activitydependent
processes
The formation of synapses in the central nervous system is a
complex process and might be regulated by multiple molecules.
The generation of specific synaptic connections is
also critically dependent on electric activity, which is important
for the fine-tuning, for the elimination of inappropriate
connections and stabilization of appropriate ones.
Neuronal circuits appear to be very sensitive to sensory
experience during specific early postnatal phases, termed
critical periods, after which plasticity is then decreased.
Furthermore, during development and throughout adulthood,
synapses are continuously structurally and functionally
reconfigured, a process that is described by the term
synaptic plasticity.
It is known that synaptic activity can induce a number of
molecular changes including posttranslational modifications
of synaptic proteins, regulation of gene activity or
secretion of proteases. It is therefore a fascinating question
how neuronal activity interacts with genetic instructions to
form and modify synapses or circuits within the nervous system.
The molecular constituents mediating these processes
are largely unknown. We therefore concentrated on the
170 Function and Dysfunction of the Nervous System