Gene essential for neuron development and contextual memory

The results are published in the journal PLoS ONE.

The birth of new neurons, a process called neurogenesis, is continuously occurring in the brain, not only during development but also during adulthood within two specialized areas, the hippocampus and the subventricular zone. Recent researches where the new neurons of the hippocampus were increased or eliminated by different ways have shown that neurogenesis is essential for the formation of memories.

These studies, however, have not yet succeeded in explaining how the newborn neurons are integrated in the existing memory circuits, and, perhaps more important, have not clarified the molecular mechanisms that coordinately govern in newborn neurons the processes of proliferation, differentiation and integration into the memory networks.

A team of researchers at the European Centre for Brain Research has given a contribution to this field, demonstrating that the gene PC3/Tis21 (also known as BTG2) is essential to the process of neurogenesis. In fact, the neuroscientists coordinated by Dr. Felice Tirone of the Institute of Neurobiology and Molecular Medicine (INMM) of CNR, in collaboration with Prof. Vincenzo Cestari of the Institute of Neurosciences of CNR-LUMSA University, and with Dr. Patrizia Longone of the Foundation S.Lucia, have now identified the essential role of a gene, PC3/Tis21, for the differentiation of the neuron.

"We have observed," Tirone explains, "that the lack of PC3/Tis21 impairs the maturation of new neurons in the subventricular zone and in the hippocampus, and from this follows a selective loss of the contextual memory, which is at the basis of the ability to link different events. In fact, the immature neuron fails to become integrated in contextual memory circuits. Conversely, other types of hippocampus-dependent memory, such as the spatial memory, remain intact, suggesting that there is a specific correlation between the final steps of neuron maturation and the contextual memory function, and also that PC3/Tis21 may regulate the timing of recruitment of the new neurons in memory circuits."

PC3/Tis21 has a dual function: it triggers the exit from cell cycle in the new neuron when this is still a proliferating progenitor, and then allows its terminal differentiation. The underlying molecular mechanism of PC3/Tis21 is in fact dual: initially PC3/Tis21 inhibits the cell cycle progression in the proliferating progenitor, and soon after directly represses the gene Id3, a key inhibitor of neural differentiation.

The role of PC3/Tis21/BTG2 in the maturation of hippocampus neurons may also suggest its implication in neurodegenerative pathologies, such as the Alzheimer's disease, where the hippocampus is one of the first brain regions damaged.

"More generally," concludes the CNR researcher, "our results show that the correct differentiation of the neuron is critical for its activation within memory circuits. In fact, a deficit of contextual or spatial memory occurs also following a transient acceleration of the differentiation of neural progenitor cells -- as shown in our previous studies -- and thus not only after a delay of differentiation, as observed here.

"We believe that these researches, through a modulation or alteration of the process of differentiation of the neuron, may create conditions uniquely apt to understand the mechanism by which the neuron is integrated into memory networks."