Lysophosphatidic Acid Involved in a Mechanism of Neuronal Hyperexcitability in Psychiatric Disorders

What's the science?

In some psychiatric disorders (e.g. schizophrenia), communication between neurons in the brain (via synapses: the connections between neurons) is altered. Lysophosphatidic acid (LPA) signaling in the brain’s synapses is also known to be altered in psychiatric disorders, leading to hyperexcitability in the brain (a loss of balance between excitation and inhibition due to increased excitation of glutamatergic (i.e. excitatory) neurons). LPA is synthesized by the enzyme autotaxin, but we don’t know what the source of LPA is in the synapse. This week in Molecular Psychiatry, Thalman and colleagues explored the source of LPA in the brain, and whether inhibition of autotaxin could control hyperexcitability in the brain.

How did they do it?

Experiments were performed using mice. First, the authors used immunohistochemistry and electron microscopy techniques to assess whether autotaxin was colocalized with excitatory or inhibitory neurons, and where in the synapse autotaxin was located. Next, they imaged astrocytes in vivo using green fluorescent protein, to assess whether autotaxin transport was occurring within astrocyte endfeet (i.e. processes) near synapses. The authors also examined knockout mice without a gene that regulates/lowers LPA levels (PRG-1-/- mice), and mice without autotaxin in astrocytes (ATXfl/fl). Finally, in a ketamine animal model of schizophrenia (ketamine induces hyperexcitability), the authors explored the potential of an autotaxin inhibitor on hyperexcitability.

What did they find?

The authors found that autotaxin was colocalized with excitatory neurons but not inhibitory neurons. Specifically, autotaxin was present in astrocyte processes at these synapses. They confirmed the location of autotaxin in astrocyte processes of both the hippocampus and cortex using electron microscopy. Using green fluorescent protein to image autotaxin, they found that it’s transport within the astrocytes was stimulated via glutamate (excitatory neurotransmitter). In mice with PRG-1 deletion (causing dysregulated LPA), autotaxin inhibition reduced excitation (excitatory post-synaptic currents) of pyramidal neurons in the hippocampus to normal levels, but in normal mice, autotaxin inhibition did not reduce excitation. This indicates that autotaxin inhibition can bring activity levels back to normal in hyperexcitable neurons. A similar observation was made when autotaxin was genetically deleted in astrocytes (ATXfl/fl mice). In a ketamine animal model of schizophrenia, ketamine caused cortical hyperexcitability as expected, while autotaxin inhibition reduced it to normal levels. Autotaxin inhibition also reduced behaviors associated with hyperexcitability such as hyperlocomotion to normal levels.

What's the impact?

In this study, the authors explored regulation of a phospholipid (LPA) known to regulate cortical excitability and be disrupted in psychiatric disorders. This study demonstrates that autotaxin from astrocytes at the synapse are likely responsible for regulating LPA levels and therefore cortical hyperexcitability. Targeting autotaxin could prove viable in reducing cortical hyperexcitability and related behavioral symptoms associated with psychiatric disorders.

Thalman et al., Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders. Molecular Psychiatry (2018). Access the original scientific publication here.

The Representation of Cost, Benefit and Gratitude in the Brain

What's the science?

What happens in the brain when we experience gratitude? Gratitude has previously been found to be associated with activity in the medial prefrontal cortex (mPFC) and perigenual anterior cingulate cortex (pACC), which are brain regions associated with value. In social interactions, how the giver perceives the cost of an action, and the receiver perceives the benefit, and how these two components are integrated in the brain, have not been studied in the context of gratitude. This week in Journal of Neuroscience, Yu and colleagues used functional magnetic resonance imaging (fMRI) to understand the experience of gratitude.

How did they do it?

The authors hypothesized that evaluation of cost and benefit would be related to activity in the mPFC (brain regions associated with valuation), and the experience of gratitude would be related to activity of the pACC. Thirty-one healthy young participants were included in data analysis. The authors first applied painful stimuli (electrical) and determined four pain levels calibrated to each individual. In the main experiment, during fMRI scanning, participants experienced many trials in which they were told they would receive a shock (at one of their four pain levels) unless their ‘partner’ in the experiment paid (at one of five payment levels, pre-determined per trial) to relieve their pain. The partner was actually a confederate, working with the experimenters.

What did they find?

The authors only analyzed trials in which the partner ‘helped’ the participant (by paying to reduce the participant’s pain). High cost (versus low cost) trials, where the partner paid more to help the participant, were associated with greater activation in the dorsomedial prefrontal cortex, right temporoparietal junction, and precuneus of the participant being helped. These regions are known to be involved in mentalizing and empathy. High benefit (partner pays to remove high pain) versus low benefit trials were associated with greater activity in regions associated with valuation; the ventromedial prefrontal cortex, and ventral and dorsal striatum. Gratitude was calculated using a formula that combined the cost and benefit for each trial together. Activity in the pgACC was found to track this measure of gratitude. pgACC activity also tracked how grateful participants reported feeling overall, at the end of the experiment. Finally, after measuring connectivity between the aforementioned brain regions, the authors found that a model in which ventral striatum and right temporoparietal junction influenced the pgACC was the best fit for the data. This suggests that gratitude is integrated in the pgACC.

Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

This is the first study to examine brain activity associated with gratitude using an index of gratitude on a trial-by-trial basis, and to consider how cost (to the helper) and benefit (to the receiver) are integrated into a perception of gratitude. The study found that cost was associated with brain regions involved in mentalizing, benefit was associated with brain regions involved in valuation, and gratitude was integrated in the pgACC. These findings help us to understand the representation of complex emotions like gratitude in the brain.

H. Yu et al., Decomposing gratitude: representation and integration of cognitive antecedents of gratitude in the brain. Journal of Neuroscience (2018). Access the original scientific publication here.

Common Genetic Variation Contributes to Migraines in Families

What's the science?

Migraine is an extremely common disorder affecting up to 20% of adults in developed countries. Migraines tend to run in families, however, the genetic risk underlying this is not well understood. A typical way to study genetic risk is to look at rare genetic mutations, which often put a person at high risk for a disease disease. However, ‘common’ genetic variations (i.e. single nucleotide polymorphisms) in the population could have a significant contribution to risk of migraine that runs in families. This week in Neuron, Gormley and colleagues test whether a genetic risk score (of common genetic variants) is associated with migraines that aggregate in families.

How did they do it?

They used a dataset including 1589 families (a total of 8319 family members) with genotype information. They generated a polygenic risk score for each individual using a set of SNPs (single nucleotide polymorphisms; commonly occurring changes in the genetic code), that were previously shown to be associated with migraine risk. They tested for the association between this polygenic risk score and risk of different migraine subtypes including migraine with aura, migraine without aura and a rare form of migraine (hemiplegic migraine) in families (using ‘logistic mixed modelling’ which controlled for sex, age and genetic relatedness) compared to a large group of controls. They also compared the risk of migraine explained by the genetic risk score in families to a large sample population of unrelated individuals with migraine.  

What did they find?

They found that the genotypes associated with risk for migraine (from the polygenic risk score) were enriched (i.e. more common) in families with all forms of migraine compared to controls. The strongest association was for the migraine with aura, followed by hemiplegic migraine and migraine without aura. In particular, a subtype of migraine hemiplegic migraine had the strongest enrichment of polygenic risk. Polygenic risk score explained 3.5% of the variance in families (for presence of migraine) compared to 1.6% variance explained (for presence of migraine) in the general population. When compared to people with migraine in the general population, family members with migraine showed a greater burden of polygenic risk (more risk variants in their genome) and this was strongest for hemiplegic migraine followed by migraine with typical aura and migraine without aura. Furthermore, in a genetic transmission test they found that in families, offspring with migraine received a higher percentage of common migraine risk variants from their parents then would be expected by chance, suggesting that these common genetic risk variants are over-transmitted to family members with migraine.

What's the impact?

This is the first study to show that common genetic variation known to associate with migraine risk, is enriched (more common) in families compared to those with migraines in the general population. Before this study, the contributions of common genetic variants to migraine risk in families was unclear. We now know that common genetic risk variants that contribute to all forms of migraine risk are transmitted through families.

Gormley et al., Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1589 Families. Neuron (2018). Access the original scientific publication here.