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New Neurons Need Input For Maturation

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Newly created neurons in adults rely on signals from distant brain regions to regulate their maturation and survival before they can communicate with existing neighboring cells–a finding that has important implications for the use of adult neural stem cells to replace brain cells lost by trauma or neurodegeneration, Yale School of Medicine researchers report.

n fact, certain important synaptic connections–the circuitry that allows the brain cells to talk to each other–do not appear until 21 days after the birth of the new cells, according to Charles Greer, professor of neurosurgery and neurobiology, and senior author of the study, In the meantime, other areas of the brain provide information to the new cells, preventing them from disturbing ongoing functions until the cells are mature.

It was established in previous studies that several regions of the adult brain continue to generate new neurons, which are then integrated into existing brain circuitry. However the mechanisms that allowed this to happen were not known.

To answer this question, Greer and Mary Whitman, an M.D./Ph.D. candidate at Yale, studied how new neurons are integrated into the olfactory bulb, which helps discriminate between odors, among other functions.

They found that new neurons continue to mature for six to eight weeks after they are first generated and that the new neurons receive input from higher brain regions for up to 10 days before they can make any outputs. The other brain regions then continue to provide information to the new neurons as they integrate into existing networks.

The discovery of this previously unrecognized mechanism is significant, said Greer, because “if we want to use stem cells to replace neurons lost to injury or disease, we must ensure that they do not fire inappropriately, which could cause seizures or cognitive dysfunction.”

J Neurosci. 2007 Sep 12;27(37):9951-61.

Synaptic integration of adult-generated olfactory bulb granule cells: basal axodendritic centrifugal input precedes apical dendrodendritic local circuits.

Whitman MC, Greer CA.

Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.

The adult mammalian olfactory bulb (OB) receives a continuing influx of new interneurons. Neuroblasts from the subventricular zone (SVZ) migrate into the OB and differentiate into granule cells and periglomerular cells that are presumed to integrate into the synaptic circuits of the OB. We have used retroviral infection into the SVZ of mice to label adult-generated granule cells and follow their differentiation and integration into OB circuitry. Using synaptic markers and electron microscopy, we show new granule cells integrating into the reciprocal circuitry of the external plexiform layer (EPL), beginning at 21 d postinfection (dpi). We further show that synapses are formed earlier, beginning at 10 dpi, on the somata and basal dendrites of new cells in the granule cell layer (GCL), before dendritic elaboration in the EPL. In the EPL, elaborate dendritic arbors with spines are first evident at 14 dpi. The density of spines increases from 14 to 28 dpi, and then decreases by 56 dpi. Despite the initial appearance of dendritic spines at 14 dpi in the EPL, no expression of presynaptic or postsynaptic markers is seen until 21 dpi. These data suggest that adult-generated granule cells are first innervated by centrifugal or mitral/tufted cell axon collaterals in the GCL and that these inputs may contribute to their differentiation, maturation, and synaptic integration into the dendrodendritic local circuits found in the EPL.

Written by huehueteotl

November 2, 2007 at 10:36 am

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