Hongjun Song and colleagues at Johns Hopkins University, Baltimore, Maryland, and the National Cheng Kung University, Tainan City, Taiwan, identified the critical period by characterizing new neurons as they matured. First author Shaoyu Ge and colleagues used retroviral vectors to label and track new dentate gyrus neurons with green fluorescent protein. They then measured the electrical properties of emerging neurons in acute hippocampal slices. They found that the ability of new neurons to mount a long term potentiation (LTP) response to theta burst stimulation depended on the cells’ age. At 1 month old, all new neurons tested exhibited LTP, as opposed to only 67 percent of 4-month-old neurons. The amplitude of the LTP response also changed with age, being low at 0.5 and 0.75 months and peaking at around 1–1.5 months. The LTP amplitude in 1-month-old neurons was about twice that of 4-month-old cells, which was about the same as that detected in mature neurons.

To examine the molecular basis of this age-dependent plasticity, the authors chose to focus on glutamate receptors, in particular the NR2B subtype because it has been implicated in the classic critical period of neurodevelopment. When Ge added the NR2B antagonist ifenprodil to 1-month-old neurons, excitatory post-synaptic currents (EPSCs) fell by 72 percent, whereas the same treatment in 4-month-old neurons reduced EPSCs cells by only 25 percent, suggesting that NR2B activity peaks in younger cells. In support of this, they found that ifenprodil abolished LTP in 1-month-old neurons, but barely dented LTP in 2-month-old or mature neurons. Looking more closely at 1-month-old neurons, when the researchers administered just enough ifenprodil to reduce EPSCs by 25 percent, LTP amplitude was significantly reduced; however, when the researchers used the general NMDAR antagonist APV to reduce EPSCs by the same amount, it did not affect LTP. The differential responses to ifenprodil and APV suggest that it is specifically the NR2B subtype of receptor that is crucial for LTP during the critical period of plasticity in emerging neurons.

This idea that new neurons have a window of opportunity to integrate into existing neural networks is not new. Most recently, Fred Gage and colleagues at the Salk Institute, La Jolla, California, demonstrated that during their first 3 weeks, new neurons extend processes to seek out electrical connections in vivo (see ARF related news story). Song and colleagues suggest that “adult-born neurons within the critical period may serve as major mediators for experience-driven plasticity and therefore function as special units in the adult circuitry to contribute to specific brain functions throughout life.”

Whether this prediction turns out to be true remains to be seen. It is at present a subject of intense debate and research, some of it contradictory. For example, the precise role of neurogenesis in the learning and memory improvements that environmental enrichment can stimulate remains unclear (see ARF related news story). Rene Hen and colleagues at Columbia University, New York, have shown that neurogenesis may be important for contextual fear conditioning but not for spatial memory (see Saxe et al., 2006) and may even be detrimental to working memory. In the March 13 PNAS, Hen and colleagues reported that two different way of ablating neurogenesis, by focal irradiation of the hippocampus or by genetically engineering the loss of neural progenitor cells, both caused an improvement in hippocampal-dependent working memory.

It is not yet clear how neurogenesis improves or weakens different forms of learning and memory. Hen and colleagues temper the exuberance surrounding neurogenesis research with a cautionary note. “Strategies aimed at stimulating hippocampal neurogenesis to elicit antidepressant or precognitive effects will need to strike a fine balance between restoring function and avoiding potential negative consequences of an excess of neurogenesis,” they write.—Tom Fagan.

References:
Ge S, Yang C, Hsu K, Ming G, Song H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron. 2007 May 24;54:559-566. Abstract

Saxe MD, Malleret G, Vronskaya S, Mendez I, Garcia AD, Sofroniew MV, Kandel ER, Hen R. Paradoxical influence of hippocampal neurogenesis on working memory. PNAS. 2007, March 13;104:4642-4646. Abstract