25 Aug 2010

Scientists know a great deal about how Alzheimer disease damages the hippocampus at a cellular and cognitive level, but surprisingly little is known about how AD affects the electrical activity of the hippocampus. In the August 18 Journal of Neuroscience, researchers led by Aline Stéphan at Paris Descartes University, France, report that Aβ dampens the electrical theta (ϑ) oscillations of the rat hippocampus, and this modulation correlates with a decline in learning ability. Stéphan and colleagues traced the change in ϑ rhythms back to a reduction in the number of ϑ-generating GABAergic neurons in the septum, which project into the hippocampus. This ϑ decline is not due to cell death, but may instead reflect a change in firing patterns, according to the data. The findings point to another mechanism by which AD may disrupt normal cognitive functions and learning, and suggests that septal inhibitory GABAergic neurons might be a target for early therapeutic intervention. The weakening of inhibitory inputs to the hippocampus, and resulting disruption of normal rhythms, also fits with recent data from some mouse models showing that the hippocampus may become hyperexcitable in AD.

“I think this work is really interesting and potentially significant,” said Christine Gall of the University of California at Irvine, who was not involved in the study. “It suggests that a loss of ϑ oscillations might be a critical part of the cellular changes that underlie cognitive impairment.”

Normal hippocampal functioning depends on synchronized firing in the 4-10 Hz range—the ϑ rhythm. The hippocampal ϑ oscillations have been found to play an important role in cognitive processes, helping to control timing in the brain and encode information (see Vertes et al., 2004). A reduction in hippocampal ϑ rhythms has been linked to reduced spatial memory in several studies (see, e.g., Chrobak et al., 1992 and Nagahara et al., 1992). Although some ϑ rhythms can be generated in the hippocampus itself, the main ϑ generators for this part of the brain are GABAergic neurons in the septum, a thin band of tissue that separates the right and left ventricles (see Sotty et al., 2003 and Borhegyi et al., 2004). These inhibitory neurons fire in rhythmic bursts.

To examine how Aβ affects ϑ rhythms, first author Vincent Villette injected Aβ40 and Aβ42 peptides, at a ratio of 2:1, into the hippocampi of healthy adult rats to mimic the seeding role of Aβ42 in promoting aggregates of Aβ40. This protocol produces amyloid plaques and inflammation in the rat brain, and injected rats demonstrate impaired synaptic plasticity and learning deficits. Human imaging studies show that amyloid load precedes cognitive dysfunction, Stéphan wrote in an e-mail to ARF, and that Aβ deposition is a primary event in the pathological cascade (see ARF related news story on Buckner et al., 2005; Engler et al., 2006; Jack et al., 2009; Mormino et al., 2009). Therefore, Stéphan believes that this injection model is well suited for studying early changes in the cognitive network involved in memory.

Villette and colleagues assessed the memory of injected rats using the novel object recognition test, a paradigm requiring intact hippocampal function (see Kumaran et al., 2006). Rats were presented with a variety of objects every other day for three weeks, with one object always being the same. While rats injected only with vehicle gradually spent less time exploring the familiar object and more time exploring the novel ones, Aβ-injected rats showed the opposite tendency, an effect that grew worse two to three weeks after the injections. In other words, the ability of Aβ-treated rats to distinguish between novel and familiar objects gradually declined.

Villette and colleagues recorded electrical activity during object exploration, when ϑ oscillations are maximal in normal rats, and found that in the Aβ-treated rats, the power of the ϑ frequencies decreased between days 9 and 21 after injections. In addition, when vehicle-treated rats learned to discriminate between a novel and a familiar object, their peak ϑ frequency dropped from about 7.5 Hz to 7.1 Hz when exploring the novel object, an effect seen in other studies (see Jeewajee et al., 2008), but in Aβ-treated rats, the ϑ frequency stayed constant at 7.6 Hz, correlating with a lack of learning.

To see what might be causing this loss of ϑ power, the authors recorded electrical activity from neurons in the septum about 25 days after Aβ injections. They found that about 40 percent fewer neurons fired in rhythmic bursts in Aβ-injected rats compared to control animals. The authors determined that this decline was not due to cell death, as they saw no differences in the number of cells expressing a neuronal marker. Villette and colleagues then examined septal neurons that were phase locked to ϑ oscillations. In vehicle-treated animals, about 90 percent of phase-locked neurons were rhythmic-bursting neurons. In Aβ-treated rats, only 60 percent of phase-locked neurons fired in rhythmic bursts, with the remainder slow-firing, leading the authors to speculate that rhythmic-bursting neurons might be converting to slow-firing neurons in Aβ-treated animals.

To further identify affected cells, Villette and colleagues combined electrophysiological recordings with immunohistochemistry. In both vehicle-treated and Aβ-treated rats, almost all rhythmic-bursting neurons were GABAergic, and in agreement with previous studies, about a third of those also expressed parvalbumin (see Hangya et al., 2009), a calcium-binding protein found in only some GABAergic cells. In Aβ-treated rats, however, the firing rates of the parvalbumin-containing GABAergic neurons were significantly lower than they were in vehicle-treated rats, and most (five out of six) slow-firing neurons were GABAergic. In contrast, only one-third of slow-firing neurons are GABAergic in control animals. “The results indicate that hippocampal Aβ accumulation selectively reduces the firing of rhythmic, GABAergic, parvalbumin-containing, septal neurons,” Stéphan wrote, “which weakens the transmission of ϑ rhythms to the hippocampus and detunes network activity.” The proper tuning of septohippocampal network activity is not only involved in memory processes, suggested Stéphan, but also exerts a neuronal protective effect by keeping network activity in the normal physiological range. “We believe that such impairments could later lead to dramatic hippocampal hyperexcitability,” she wrote. The results help explain why hippocampal hyperactivity is seen in some transgenic mouse models of AD (see ARF related news story on Palop et al., 2007), and perhaps even why people with AD are more susceptible to seizures.

A reduction in normal hippocampal rhythms could lead to more spontaneous and asynchronous firing, Gall said, and the next experiment would be to record unit firing to determine if excitability is actually changing in these Aβ-treated rats. Loss of ϑ rhythms could be harmful in other ways, Gall said, pointing out that ϑ rhythms are also important for maintaining BDNF signaling (see ARF related news story). Decreased BDNF signaling would likely impair both cell viability and memory encoding. Gall said that another intriguing question is how Aβ accumulation in the hippocampus is able to affect neurons in the septum. One possibility is that Aβ changes the electrophysiological drive to the septum from the hippocampus, and that leads to the loss of bursting cells, suggested Gall. Another possibility is that Aβ reduces the production of growth factors that are normally taken up by septal axons and relayed back to septal cells, she said.

One of the most interesting implications of the study is that restoring ϑ rhythms could be therapeutic in early AD. Stéphan wrote that they plan to identify the slow-firing neurons seen in Aβ-treated rats, and pharmacologically restimulate them with GABA or glutamate receptor agonists. They hope that this will reactivate rhythmic bursting activity, restore the hippocampal ϑ rhythm to full power, and reinstitute memory functions. If they are successful, it would suggest that stimulation of the septohippocampal pathway could be a viable therapeutic approach for AD.—Madolyn Bowman Rogers

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References

News Citations

1. Network News: Images of AD Brains Reveal Widespread Snafus 26 Sep 2005
2. Do "Silent" Seizures Cause Network Dysfunction in AD? 7 Sep 2007
3. BDNF—Learning Boosts Trophin Signals in Hippocampus 11 Mar 2010

Paper Citations

1. Vertes RP, Hoover WB, Viana Di Prisco G. Theta rhythm of the hippocampus: subcortical control and functional significance. Behav Cogn Neurosci Rev. 2004 Sep;3(3):173-200. PubMed.
2. Chrobak JJ, Napier TC. Antagonism of GABAergic transmission within the septum disrupts working/episodic memory in the rat. Neuroscience. 1992;47(4):833-41. PubMed.
3. Nagahara AH, McGaugh JL. Muscimol infused into the medial septal area impairs long-term memory but not short-term memory in inhibitory avoidance, water maze place learning and rewarded alternation tasks. Brain Res. 1992 Sep 18;591(1):54-61. PubMed.
4. Sotty F, Danik M, Manseau F, Laplante F, Quirion R, Williams S. Distinct electrophysiological properties of glutamatergic, cholinergic and GABAergic rat septohippocampal neurons: novel implications for hippocampal rhythmicity. J Physiol. 2003 Sep 15;551(Pt 3):927-43. PubMed.
5. Borhegyi Z, Varga V, Szilágyi N, Fabo D, Freund TF. Phase segregation of medial septal GABAergic neurons during hippocampal theta activity. J Neurosci. 2004 Sep 29;24(39):8470-9. PubMed.
6. Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. PubMed.
7. Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Långström B, Nordberg A. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2856-66. PubMed.
8. Jack CR, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Shiung MM, Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC, . Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain. 2009 May;132(Pt 5):1355-65. PubMed.
9. Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, Koeppe RA, Mathis CA, Weiner MW, Jagust WJ, . Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain. 2009 May;132(Pt 5):1310-23. PubMed.
10. Kumaran D, Maguire EA. The dynamics of hippocampal activation during encoding of overlapping sequences. Neuron. 2006 Feb 16;49(4):617-29. PubMed.
11. Jeewajee A, Lever C, Burton S, O'Keefe J, Burgess N. Environmental novelty is signaled by reduction of the hippocampal theta frequency. Hippocampus. 2008;18(4):340-8. PubMed.
13. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.

Further Reading

News

1. Network News: Images of AD Brains Reveal Widespread Snafus 26 Sep 2005
2. BDNF—Learning Boosts Trophin Signals in Hippocampus 11 Mar 2010
3. Do "Silent" Seizures Cause Network Dysfunction in AD? 7 Sep 2007