Young, restless neurons may bully their elders

Neurogenesis--the birth and integration of neurons--occurs in the adult brains of all mammals, including humans. I've posted on the phenomenon of adult neurogenesis here and here, and it happens to the focus of my thesis in grad school. One of the major issues in the field is how the generation of new neurons translates into a functional change in the brain. Birth is the first of a number of daunting challenges: new cells must then survive, make connections, and integrate into the circuitry of the mature brain. It is this last undertaking--joining existing networks without disrupting the circuit--which has proved the most conceptually challenging.

Since Alan Turing and the dawn of computer science, the prevailing model of the brain has been based on a computer analogy. The networks of neurons composing the brain were likened to the hard-wired circuits of computer hardware, cemented in place at an early age. Plasticity, which refers to the brain's ability to learn and adapt to the environment, was attributed solely to changes occurring within the operating circuitry, between its existing components (i.e. synaptic plasticity). In line with the computer analogy, this synaptic plasticity is thought to resemble the process of changing computer operations by adding software, which operate within the context of a hard-wired network and thus do not require structural reorganization of the circuitry.

Although synaptic plasticity is a crucial mechanism underlying the brain's remarkable adaptive capabilities, it is not the only mechanism. In the 60s and 70s, theories of structural plasticity, such as axonal elongation and synaptic reorganization, began to emerge and gradually creep into the analogy with computers. However, these activities involved neural pathways being reorganized between existing neurons; new neurons continued to be excluded from the conceptual framework.

About a decade ago, adult neurogenesis finally gained widespread acceptance in the scientific community, initiating a gradual shift in the concept of brain plasticity and adaptability. These new neurons, which integrate into existing neural networks, provided a previously unrecognized, and far more dramatic, form of structural and functional plasticity. The crucial question of how new neurons impact the adult neuronal circuitry remains a challenge, and is dictated by two parameters: their physiological properties and their synaptic connectivity.

Recent work has shown that new neurons in the adult hippocampus (a structure crucial for the formation of memories, and one of the two major locations of adult neurogenesis) have unique physiological properties: they are more excitable (i.e. more likely to fire action potentials subsequent to a given stimulation) and have an enhanced potential for synaptic plasticity. But what about their connectivity? Do the existing neurons send out new axons to accommodate new neurons, or do the new neurons incorporate themselves into the existing circuits?

New findings from Rusty Gage’s lab at the Salk Institute for Biological Sciences, published their results online last week in Nature Neuroscience, support the latter. The researchers tracked the fate of newborn neurons by injecting a retrovirus engineered to carry the gene for green fluorescent protein (GFP) into the hippocampus. This technique is useful because retroviruses can only infect dividing cells (with the exception of lentiviruses like HIV, which can infect nondividing cells such as mature neurons). Thus, cells that dividing at the time of the injection, including newly born neurons, are labeled green, and can be tracked as they make the initial connections with the existing hippocampal circuitry.

They used an impressive combination of high-resolution imaging techniques to examine the fine structural details of the emerging connections pioneered by these new neurons. Their analysis allowed them to digitally reconstruct synapses during formation, and showed that initially, new neurons send out small protrusions, called filopodia, to make contact with synapses that already exist between two "older" neurons. When the filopodia mature, they become functional dendritic "spines," which are small protrusions from dendrites that actually participate in synaptic communication. Thus, the new neurons join into a preexisting synapse, forming a "multi-synapse" connection, suggesting that new neurons are making connections with established networks.

Once they've elbowed their way into an existing communication, the new neurons take their intrusion up another notch. As the neurons aged, they became less likely to be involved in "multi-synapse" connections, and concomitantly more likely to be involved in single-synapse connections. This suggests that the formerly multi-synapse connections were transforming into single-synapse connections; in other words, new neurons were taking over the connections of older neurons, effectually replacing those neurons in a particular part of the circuit. The Gage lab has previously shown that new neurons depend on neuronal input to survive; it's possible that new neurons have to compete with older neurons for those connections, and that their unique physiological properties may give them a competitive advantage.

This hypothesized replacement mechanism, which must still be tested by live-cell imaging, makes the incorporation of new neurons into functional networks easier to conceptualize. Instead of forming new circuits willy-nilly, or forcing old networks bring them in, new neurons muscle their way into the established circuitry, occasionally replacing older, less vigorous neurons. One of the implications here is new neurons may be able to functionally replace dead or dying neurons in neurodegenerative diseases such as Parkinson's or Alzheimer's. Further, these new neurons, with their enhanced plasticity, may continually "reinvigorate" an old hippocampus, even in healthy adults, allowing learning and memory to continue at higher levels that would otherwise be possible.

Reference:
Toni N, Teng EM, Bushong EA, Aimone JB, Zhoa C, Consiglio A, van Praag H, Martone ME, Ellisman MH, Gage FH. Synapse formation on neurons born in the adult hippocampus. Nature Neuroscience. 2007, May 7. Advanced online publication.