8 June 2012. Scientists believe that Abeta weakens synapses early in the course of Alzheimer’s disease–but how early? In the June 6 Journal of Neuroscience, researchers led by Brad Hyman at Massachusetts General Hospital, Charlestown, report that AD mice as young as one month already show measurable defects in synaptic plasticity. To demonstrate this, Hyman and colleagues used ocular dominance in the visual cortex, a well-studied paradigm of plasticity. The researchers found abnormalities in the transgenic mice when they occluded vision in one eye during the critical period of visual development. In normal mice, this leads neurons connected to the good eye to step up their synaptic activity; the open eye may also annex more territory in the visual cortex in the absence of competition from the other eye. However in the AD mice, neurons failed to increase their activity or make new synaptic contacts.
"This paper pushes the detection of synaptic changes very early," said Ahmad Salehi at Stanford University Medical Center, Palo Alto, California. He was not involved in the research. "What we learn is you have to challenge [neurons] to see [early deficits]. You will not be able to see them just by comparing transgenic versus nontransgenic."
In recent years numerous studies have shown that soluble, oligomeric forms of Abeta damage synapses, crippling their ability to change in response to experience (see, e.g., ARF related news story; ARF news story; ARF news story ; and ARF related news story). Adding Abeta to hippocampal cultures blocks long-term potentiation, the primary form of synaptic plasticity (Lambert et al., 1998; Chen et al., 2002; Walsh et al., 2002). Hyman and colleagues wondered how early such deficits might be detectable in vivo.
To study this, first author Christopher William tested ocular dominance plasticity using two different mouse models that express human APP with the Swedish mutation, APP/PS1 and Tg 2576. These animals do not show cognitive deficits until three months of age, while the critical period for visual development occurs in the fourth and fifth weeks of life. William and colleagues first verified, using immunoprecipitations and immunohistochemistry, that APP and Abeta were present in the brains of one-month-old transgenics. Then the authors employed two different methods—gene induction and optical intrinsic signal imaging—to look at activity in the visual cortex.
The first method involves exposing the animals to 30 minutes of light after 15 hours in darkness, while covering one eye. In response, neurons in the visual cortex that are driven by the open eye pump up transcription of the Arc gene, which is involved in synaptic plasticity. By sacrificing the mice and looking at brain sections, researchers can see the pattern of functional connections at cellular resolution based on Arc mRNA expression. The authors found that transgenic APP mice and their nontransgenic littermates responded equally well to visual stimuli when both eyes were open and showed normal functional organization of the visual cortex. After either four or 10 days of monocular vision, however, it was a different story. While the area driven by the open eye expanded noticeably in nontransgenic animals, it failed to do so in either line of AD mice.
To measure the magnitude of the visual response, the authors turned to intrinsic signal imaging in awake mice. In this method, animals view moving patterns on a LCD monitor while researchers assess small changes in autofluorescence (reflecting metabolic activity) in neurons of the visual cortex through a cranial window. The authors covered one eye for four days, then opened it for testing. Neurons in control mice showed the expected activity changes, with those connected to the deprived eye less active than before visual occlusion, indicating that long-term depression had occurred. In contrast, activity in neurons connected to the nondeprived eye slightly strengthened. AD mice responded abnormally; although neurons connected to the deprived eye weakened, so did those connected to the normal eye, suggesting that ocular dominance plasticity failed. Together with the Arc induction data, the results make the case for an early synaptic plasticity defect in AD mice, the authors conclude.
Salehi noted that this system could provide a new tool for testing therapeutic interventions. “The method looks quite quantitative. You could easily see the effects of drugs,” he suggested.
What do the data imply for human disease? People with Down’s syndrome carry an extra copy of the gene for APP, leading to life-long elevated levels of the protein. These synaptic plasticity defects could be relevant to developmental abnormalities in this condition, the authors suggest. However, Salehi pointed out that AD mice overexpress APP at much higher levels than are present in Down’s syndrome brains. For AD, the data dovetail with other findings in the field that suggest that synaptic deficits occur a decade or more before dementia begins. “This tells you that small alterations in synaptic function occur much earlier than what we observe in terms of structural changes,” Salehi noted. The ocular dominance data may provide a glimpse into early AD pathology, suggested Thomas Arendt at Universität Leipzig, Germany, writing to Alzforum, “The present study adds an important piece of evidence to the concept that a failure of synaptic reorganization is of utmost critical importance in the AD pathomechanism.” (See full comment below.)—Madolyn Bowman Rogers.
William CM, Andermann ML, Goldey GJ, Roumis DK, Reid RC, Shatz CJ, Albers MW, Frosch MP, Hyman BT. Synaptic plasticity defect following visual deprivation in Alzheimer’s disease model transgenic mice. J Neurosci. 2012 Jun 6;32(23):8004-11. Abstract