Pathological proteins likely harm cognition by acting on synapses, but the details of how these proteins impair transmission largely remain a black box. In the March 4 Neuron, researchers led by Edward Stern at Bar-Ilan University in Ramat Gan, Israel, shed some light on how toxic tau might affect communication at the network level. In young tau model mice, cortical neurons fired more slowly than in controls, dampening network activity, the authors report. This seemed to be due to poor coordination of excitatory neurons, which made it harder for downstream cells to depolarize and fire. Notably, only a handful of neurons contained detectable tau tangles at this age. The data demonstrate that disrupting the timing of only a small percentage of neurons can degrade entire networks, Stern said. These young mice have spatial memory deficits, implying that the network alterations suffice to cause mild cognitive problems. The data also hint at new approaches for ameliorating cognitive symptoms in tauopathies such as frontotemporal dementia and Alzheimer’s disease, Stern noted.
“This is a fantastic paper. People have not seen this hypoexcitability at an early age before,” Kishore Kuchibhotla at New York University Langone Medical Center told Alzforum. He was not involved in the research.
Numerous studies have reported that toxic tau harms synapses, and accumulating evidence is pointing to soluble forms of the protein rather than neurofibrillary tangles (see Jul 2005 news; Feb 2007 news; Mar 2013 conference news). To measure the effects of tau on overall network activity, most previous work employed acute brain slices. Researchers found hyperexcitable neurons, particularly in slices from older mice in whch many neurons had already died (see Crimins et al., 2011; Crimins et al., 2012).
Stern wanted to assess network function at an earlier point in time, when, at least in mice, the cognitive deficits start to appear but neurons are still healthy. At this stage, therapeutic interventions might be most effective, Stern told Alzforum. He also wanted to study live animals, which better model what happens in the intact brain. He chose rTg4510 mice, which express human tau containing the P301L mutation linked to familial frontotemporal dementia. The mice develop spatial memory problems and sparse tau tangles in the cortex by 2.5 months, but do not lose cortical neurons until 8.5 months, when the pathology is more pronounced.
First author Noa Menkes-Caspi inserted electrodes into the frontal poles of the cortices of 5-month-old animals, and recorded electrical activity in excitatory pyramidal neurons and local field potentials as the mice sat quietly or slept. The membrane potentials of these neurons normally oscillate from hyperpolarized to depolarized at regular intervals, particularly during slow-wave sleep when network activity is highly synchronized. In the transgenics, potentials oscillated more slowly than in controls, and the difference was most pronounced during slow-wave sleep. Transgenic neurons spent more time in the hyperpolarized, “down” state, and took longer to transition to the depolarized, “up” state in which action potentials can occur. Once in the up state, transgenic neurons fired fewer action potentials, with longer delays between them, than controls did. The net effect of these changes was an overall dampening of network activity in transgenic mice.
What might cause this? The authors found that transgenic neurons experienced more “false up” transitions, in which the membrane depolarized slightly but not enough to trigger the up state—likely because transgenic neurons received insufficient synchronized synaptic inputs from upstream neurons to depolarize on schedule, Stern said. Because the mice at this young age still appear to have a normal complement of spines and synapses, the problem likely arises from faulty timing of synaptic inputs, he said. Tau in afferent neurons might interfere with transmission of information along axons, changing the timing of these inputs, Stern speculated.
This study did not address what form of tau caused the disruptions. However, only a handful of neurons in 5-month-old transgenic mice had detectable tangles. Neurons in 3-month-olds had far fewer tangles but showed similar, although less pronounced, decreases in firing. Kuchibhotla noted that the data fit with the idea that smaller species of tau, such as oligomers, may be the toxic entity.
The finding of reduced activity in these tau mice contrasts with data from amyloid models, where neurons frequently become hyperexcitable (see Sep 2007 news; Nov 2009 conference news; Aug 2012 news). The full picture of Alzheimer’s disease is likely more complex, as a previous study found areas of both hypo- and hyperexcitability in the brains of AD model mice (see Sep 2008 news). In Alzheimer’s brains, both amyloid and tau pathology occur together, and tau tends to track more closely with neuronal activity as measured by FDG-PET (see Feb 2015 conference news). Stern will next investigate how network activity fluctuates in a mouse model that includes both pathologies.
Stern also wants to know whether restoring normal activity can ameliorate cognitive symptoms. Several drugs that block calcium or potassium channels raise or lower neuronal firing. Stern plans to test cocktails of these drugs in mouse models to see if he can rescue neuronal function.—Madolyn Bowman Rogers
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- In Pursuit of Toxic Tau
- Do "Silent" Seizures Cause Network Dysfunction in AD?
- Chicago: AD and Epilepsy—Joined at the Synapse?
- Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
- Hyperactive Neurons and Amyloid, Side by Side
- What If It’s Not Garden-Variety AD? Telling Variants Apart by Where Tau Is
Research Models Citations
- Crimins JL, Rocher AB, Peters A, Shultz P, Lewis J, Luebke JI. Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy. Acta Neuropathol. 2011 Nov;122(5):551-64. PubMed.
- Crimins JL, Rocher AB, Luebke JI. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol. 2012 Dec;124(6):777-95. PubMed.
- Menkes-Caspi N, Yamin HG, Kellner V, Spires-Jones TL, Cohen D, Stern EA. Pathological tau disrupts ongoing network activity. Neuron. 2015 Mar 4;85(5):959-66. Epub 2015 Feb 19 PubMed.