Apical Dendrite - Development

Development

Dendritic arbor formation for pyramidal neurons in the cortices occurs progressively beginning in late embryonic stages of development and extending well into post-natal periods. Many dendrites of pyramidal neurons in deep layers branch and form connections in layer IV, while some extend to more superficial layers. Pyramidal cell dendrites in layer III branch to form arbors in layer I. Thalamocortical afferents will make synaptic contact with dendrites in layer IV while myriad of other inputs will meet dendrites in layer I. The post-synaptic structure is driven in part by signals from incoming afferent fibers and through life there is plasticity in the synapses.

The formation of these arbors is regulated by the strength of local signals during development. Several patterns in activity control the development of the brain. Action potential changes in the retina, hippocampus, cortex, and spinal cord provide activity-based signals both to the active neurons and their post-synaptic target cells. Spontaneous activity originating within neuronal gap junctions, the cortex sub-plate, and sensory inputs are all involved in the cell signaling that regulates dendrite growth.

Useful models of dendritic arbor formation are the Xenopus tadpoles, which are transparent in early stages of larval development and allow for dye-labeled neurons to be repeatedly imaged in the intact animal over several weeks. It has been observed from this and other models that there are rapid dendritic branch additions and retractions which lengthen the overall dendrite and accumulate more branches. This mirrors the development of axonal branches (both have a lifetime of approximately 10min). This activity decreases as neurons mature. Signals including glutamate from axon branches may increase branch additions.

Within the Xenopus tadpole model, several signaling systems have been studied. For example, in optical tectal neurons, dendrite arbor growth occurs approximately at the onset of retinal input. Many on the caudal tectate have “silent” synapses which are modulated only by N-methyl-D-aspartate (NMDA) receptors. As neurons mature, alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors are added, increasing synaptic transmission. Neuron and dendrite development are NMDA dependent. Rapidly growing dendrite arbors are more dynamic than slowly growing ones and dendrites themselves play an active role in their own development. It has been shown in studies that transport of HCN (hyperpolarization activated cyclic nucleotide) gated channel isoforms to dendritic fields of CA1 pyramidal neurons in the hippocampus occurs in an age-specific manner in the developing hippocampus.

Among the signals studied in this system is CaMKII a calcium/calmodulin-regulated serine/threonine kinase which is required for induction by not expression of long-term potentiation. CaMKII mRNA is targeted to dendrites and both protein synthesis and enzyme activity are increased by strong synaptic input. Expression in Xenopus indicates that it is associated with the transition to slowed arbor growth. This suggests that activity promotes the reduction of dendrite branch growth and retraction, stabilizing the arbor configuration. The following pattern emerges for this system:

1. Branches with NMDA-only receptors mature and recruit AMPARs, which stabilize the branches.
2. These stable branches then add new branches with NMDAR-only synapses which either stabilize through AMPARs or retract. AMPAR additions are present in adults and account for synaptic plasticity.
3. CaMKII strengthening of signals results from the selective trafficking of GluR1 AMPARs into synapses. In long term depression (LTD) the GluR subunits of AMPARs undergo endocytosis.

Temporal differences in signaling over the course of neuron maturation suggest that the most promising studies of arbor development and synaptogenesis in the future are going to occur in intact brain systems.

Another model studied in apical dendrite development is the rat. Injection of tetanus toxin into neonatal rats has shown that growth of apical dendrites occurs normally during signal deprivation while basal dendrite growth is restricted. This indicates that neural activity is critical to new dendrite formation.

However, animal models may be insufficient to elucidate the complexity of these systems. Pyramidal cells in CA1, for example, are 30 times as thick in humans as they are in rats. The entorhinal cortex is also subdivided into as few as 8 and as many as 27 sections in humans (depending on the system used), whereas there are only 2 in rats and 7 in monkeys. The connections of the dentate gyrus and entorhinal cortex are also more sophisticated in humans. In rats and cats, a very large reciprocal connection exists between the entorhinal cortex and the olfactory system. In primates this connection is absent and there are highly differentiated connections between the multimodal parasensory and paralimbic cortices and the EC which are not as evident in rats and cats. The increased size of the primate subiculum may proportionally enhance its effects on the entorhinal cortex.