Synapse formation in mouse models of AB

Alejandro Schinder, PhD
Fundación Instituto Leloir (Buenos Aires, Argentina)
Year Awarded:
2007
Grant Duration:
April 1, 2007 to March 31, 2010
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2007078
Award Type:
Pilot
Award Region:
International

Impaired Synaptogenesis as an Early Event in AD

Summary

Our goal is to study the effects of Ab on synapse formation and function in the hippocampus of adult mice in vivo. We are using a novel strategy based on the fact that new neurons are continuously generated in the adult hippocampus and go through an intense period of synapse formation. We manipulate the genetic information of those adult-born neurons to increase their levels of Ab and analyze their development and maturation using electrophysiology and microscopy.

Details


The complexity of the human brain can be easily conceived if we think about 1011 neurons connected by 1015 synapses. Those connections are highly dynamic. Synapses are continuously formed and eliminated in a manner that depends on the activity of brain circuits. Activity-dependent remodeling of neuronal networks is essential for higher brain functions. Its impairment has been associated with mental retardation syndromes and may also play an important role in neurodegenerative disorders. Alzheimer's disease (AD) has been associated with amyloid plaques, neurofibrillary tangles and neuronal death, which were thought to be the cause of cognitive decline. Recently, animal models of AD have taught us that amyloid-beta (Ab) peptides can impair synaptic transmission in the absence of plaques or tangles, but the specific effects and sites of action of Ab remain unknown. Does Ab impair neuronal communication and/or synapse formation and elimination? Our goal is to study the effects of Ab on synapse formation and function in the hippocampus of adult mice in vivo. We are using a novel strategy based on the fact that new neurons are continuously generated in the adult hippocampus and go through an intense period of synapse formation. We manipulate the genetic information of those adult-born neurons to increase their levels of Ab and analyze their development and maturation using electrophysiology and microscopy. Addressing these questions will contribute to the better understanding of the early changes underlying cognitive impairment in AD and other neurodegenerative diseases.

Publications

Laplagne, D.A., Kamienkowski, J.E., Esposito, M.S., Piatti, V.C., Zhao, C., Gage, F.H., and Schinder, A.F.(2007). Similar GABAergic Inputs in Dentate Granule Cells Born During Embryonic and Adult Neurogenesis. Eur J Neurosci. 25(10):2973-2981. Epub 2007 May 17.  

Morgenstern N.A., Lombardi G., and Schinder A.F. (2008). Newborn granule cells in the aging dentate gyrus. J. Physiol. (Lond.) 586, 3751- 7.  

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