Ripples During Slow-Wave Sleep Re-balance Neurons

What's the science?

Synapses in the brain are strengthened while awake and synaptic depression (weakening of the synapses) occurs during slow-wave sleep to rebalance synapses. This synaptic depression may help to selectively preserve memories, however, how it occurs during sleep is unclear. During slow-wave sleep, the hippocampus emits high frequency oscillations called “sharp-wave ripples” which reactivate the neurons involved in recent memories. Ripples could be required for synaptic depression during sleep, making “room” for new memories to form. This week in Science, Norimoto and colleagues test whether ripples are required for synaptic depression and subsequent memory formation in mice.

How did they do it?

They silenced sharp-wave ripple events during slow-wave sleep using optogenetic-feedback (i.e. every time a ripple event was detected, they inhibited the hippocampal neurons to reduce firing) in a group of test mice. They then recorded excitatory postsynaptic potentials (activity in the postsynaptic neurons) during slow-wave sleep and compared the test mice to control mice to determine whether synaptic depression during sleep was affected in the test mice. Mice then underwent a spatial object-recognition task. First, they explored an area containing two new objects, and then returned to the same location 2 hours later where one of the objects had moved. The authors compared the memory performance between test and control mice to determine whether disrupting the ripples had an effect on new memory acquisition.

What did they find?

The authors were able to successfully reduce almost all of the ripple events in the test mice. Control mice experienced depressed postsynaptic activity representing the expected synaptic depression that occurs during slow-wave sleep, while mice with the impaired ripple events did not show synaptic depression. Control mice showed normal memory performance, while mice with impaired ripple events were unable to identify a moved object in the spatial object recognition task, suggesting that they could not form new memories. The authors were also able to replicate the lack of synaptic depression by testing the effects of disrupting ripples in hippocampal tissue slices. They used in vitro and in vivo experiments to show that synaptic depression occurring during slow-wave sleep is mediated by NMDA receptors.

What's the impact?

This is the first study to link sharp-wave ripples during slow-wave sleep with synaptic depression and memory performance. Before this study, we did not understand the mechanism through which synaptic depression occurred during slow-wave sleep. We now know that ripples during slow-wave sleep are critical for balancing of synapses and for new memory formation.

H. Norimoto et al., Hippocampal ripples down-regulate synapses. Science (2018). Access the original scientific publication here.

Ketamine Blocks Burst Firing to Provide Depression Relief

What's the science?

Ketamine is a drug that binds to and blocks NMDA receptors found on neurons. It provides fast acting and sustained relief of depression symptoms, however, the mechanisms underlying ketamine’s effectiveness are unknown. A brain region called the lateral habenula, involved in reward processing and negative emotions, is known to have abnormal “burst” activity in patients with depression. This week in Nature, Yang and colleagues determine whether abnormal activity in the lateral habenula can drive depression-like behaviours, and how this might be reversed by ketamine.

How did they do it?

They tested to see if ketamine infusion into the lateral habenula relieved depression symptoms (improved mobility in the forced swim test) in learned helpless (depressed) rats. Next, they performed whole-cell patch-clamp (a method used to measure the electrical currents in a neuron) on lateral habenula neurons to determine : 1) whether the spontaneous neuronal activity in these cells is abnormal in depressed rats, 2) whether these abnormalities could be reversed by NMDA blockers and, 3) if changing the resting state membrane potential of the cell can alter the pattern of spiking activity in the lateral habenula. They then used optogenetic techniques to mimic the bursting activity seen in the lateral habenula of depressed mice to determine whether this activity was sufficient to induce depression behaviours.

What did they find?

Ketamine administered in the lateral habenula alleviated the depression symptoms in rats. Increased burst firing occurred in neurons in the lateral habenula of depressed rats. These burst patterns were completely blocked by ketamine, but not by other typically used antidepressant drugs. The bursting properties of the lateral habenula could be altered by changing the membrane potential of the cell, suggesting a new potential therapeutic target, the T-type calcium channel. They were also able to induce depression-like symptoms in rats by using optogenetics to control the pattern of burst firing in the lateral habenula.

What's the impact?

This is the first study to describe the mechanisms by which ketamine has fast acting depression relief. We now know that burst firing underlies depressive symptoms in rats, and that this can be blocked with ketamine. Understanding how and where ketamine acts in the brain is an important step towards developing new therapies for depression.  

Yang et al., Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. (2018). Access the original scientific publication here.

Rachel Bosma, PhD contributed to this BrainPost

Dyskinesias in Parkinson’s disease are Caused by a Subgroup of Neurons

What's the science?

In Parkinson’s disease, dopamine neurons in the midbrain degenerate resulting in problems with body movement. A dopamine medication called levodopa can be very effective for improving symptoms, however, in some cases it causes involuntary movements called dyskinesias. We know that unwanted neural activity in brain regions such as the striatum, motor cortex and sensorimotor cortex may be involved, but the specific brain region and cells causing dyskinesias are not known. Recently in Neuron, Girasole and colleagues identify a subgroup of neurons responsible for dyskinesias.

How did they do it?

They first used a method called Targeted Recombination in Active Populations (TRAP) in transgenic (genetically modified) mice. TRAP allows certain proteins (acting as labels) to be expressed in active neurons (as opposed to inactive neurons). In mice with levodopa-induced dyskinesias, they identified neurons that were active during the dyskinesias compared to control mice. Second, they then used optogenetics: Controlling neuron activation by shining light on genetically modified neurons of interest. This allowed them to inhibit and activate these specific neurons in the mice to see if they played a causal role in dyskinesias.

What did they find?

Only neurons in the striatum were significantly more active during dyskinesias compared to control mice. When examining these neurons more closely, they found that most of the active neurons were medium spiny neurons (a specific cell type of neuron found in the striatum) that were part of the 'direct pathway', an inhibitory pathway involved in motor function that is defective in Parkinson’s disease. When these neurons were inhibited with optogenetics, the dyskinesias were reduced. Inhibiting the activity of neurons in the motor or sensorimotor cortices did not reduce dyskinesias, demonstrating a causal role for striatal neurons in producing medication-induced dyskinesias.

Images are generated by Life Science Databases(LSDB)., Striatum, colour by BrainPost, CC BY-SA 1.0

What's the impact?

This is the first study to identify the neurons within the striatum that cause dyskinesias in mice. Dyskinesias are a detrimental side effect of levodopa in Parkinson’s disease and can be debilitating to patients who experience them. Understanding which neurons cause dyskinesias brings us one step closer to finding a way to treat them.

Reach out to study author Ally Girasole on Twitter @AllyGirasole

A. E. Girasole et al., A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia. Neuron. 97, 1–9 (2018). Access the original scientific publication here.