Numerous studies suggest that toxic Aβ thwarts learning and memory by blocking long-term potentiation (LTP), a process that strengthens synapses by beefing up numbers of excitatory neurotransmitter receptors. However, no one has put their finger on exactly how Aβ might pull that off. Now, researchers led by Daniel Madison, Stanford University, California, report in the June 18 Neuron that Aβ locks inhibitory mechanisms in place by blocking cannabinoid signaling that normally would tone down synaptic inhibition. This undermines excitatory signals and suppresses both LTP and another mechanism of plasticity called E-S potentiation. “The study provides an explanation for the vast literature that says LTP is reduced in the presence of Aβ,” Madison told Alzforum. “Aβ is not working on the LTP directly, but rather it’s preserving synaptic inhibition, which in turn opposes LTP.”
Aβ has also been shown to impair long-term depression or LTD (see Kuwabara et al., 2014), but Madison’s study did not address that aspect of plasticity.
Outside scientists contacted about this paper found it interesting. “The ability of Aβ to disrupt E-S potentiation is potentially relevant to interpreting the overall effects of Aβ on CNS plasticity,” Michael Rowan, Trinity College Dublin, wrote to Alzforum in an email. “The study certainly highlights the need to look at endocannabinoids more closely to explain and target presumed AD brain plasticity deficits.”
First author Adrienne Orr and colleagues used rat hippocampal slices to try to replicate the Aβ-induced loss of LTP that many had previously observed (see Chen et al., 2000; Rowan et al., 2004; Freir et al., 2001). In doing so, they noticed that Aβ more strongly prevented E-S potentiation. This refers to the improved efficiency with which incoming synaptic inputs can stimulate outgoing action potentials in a given neuron. Scientists induce E-S potentiation similarly to LTP, by administering a tetanic stimulus to provoke neurons to fire many times in quick succession. Knowing that hippocampal E-S potentiation relies on relieving GABAergic inhibition, a process also known as disinhibition (see Staff and Spruston, 2003), Madison and colleagues decided to test if Aβ disrupts that process.
When the group applied 500nM synthetic Aβ to hippocampal slices from male rats, a tetanic stimulus did not block neurons’ inhibitory inputs. Because this left inhibitory input intact, the cell bodies depolarized less and E-S potentiation did not occur. This Aβ-sensitive disinhibition reminded the researchers of a previously described process called depolarization-induced suppression of inhibition (DSI). In DSI, a neuron releases endocannabinoids back onto connecting inhibitory presynaptic terminals to bind cannabinoid receptors (CBR1). This binding reduces presynaptic calcium influx and tames GABA release to dampen inhibitory inputs. The researchers wondered if the Aβ suppression of E-S potentiation was also cannabinoid-related.
To find out, they applied a CBR1 inhibitor called AM251 to the hippocampal slices. As with Aβ, disinhibition after tetanic stimulation fell, as did E-S coupling. AM251 applied with Aβ had no added effects, suggesting the two worked on the same pathway. Aβ also blocked the inhibition-suppressing effects of a cannabinoid agonist called ACPA. However, the authors found that Aβ does not bind CBR1, suggesting it works downstream of the receptor, Madison told Alzforum. All in all, the results suggest that Aβ disrupts some aspect of cannabinoid-mediated disinhibition, which leads to deficiencies in both E-S potentiation and LTP, he said. “We hypothesize that this blockade of the cannabinoid system may be the substrate for early learning deficits in Alzheimer’s disease,” said Madison. “If we can find the exact target on which Aβ is working, we can start thinking about ways to intervene.” The next step will be to explore potential downstream candidates, he added.
“The authors provide new clues about AD pathology and support the relevance of endocannabinoid system as potential therapeutic target,” Ester Aso Pérez, Hospital Universitari de Bellvitge, Barcelona, Spain, wrote to Alzforum in an email. “Growing evidence supports the multiplicity of actions of cannabinoids and suggests CB-based therapies in the treatment of certain dementias.”
Roberto Malinow, University of California, San Diego, agreed. “The results are interesting and of potential relevance to the disease,” he wrote to Alzforum in an email. However, Malinow cautioned that all laboratories should draw on a centralized repository of Aβ so that results are comparable across studies. The lack of standardization of Aβ preparation has become a major problem for the field (see Oct 2011 Webinar).
“The phenomenon they describe is quite interesting,” echoed Tibor Harkany, Karolinska Institutet, Stockholm, in an email to Alzforum. “The case is mounting for endocannabinoids to be considered as a key target in Alzheimer's disease.” He cautioned, however, that this particular model may have limited relevance for AD, as in disease, microglia become another source of endocannabinoids, especially near amyloid plaques. Harkany wondered whether amyloid might be affecting trafficking or cell-surface availability of the CBR1 receptor, and perhaps other receptors as well.—Gwyneth Dickey Zakaib
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