A new study published in Acta Physiologica suggests that one gene may play a big role in how animals react to social situations. Researchers in Austria found that zebrafish missing a gene called lrrtm4l1 were less aggressive and more anxious than normal fish. This gene is similar to one found in humans, and the results suggest it may help shape how the brain handles emotions and social behavior. The study provides clues about how certain mental health traits might be linked to brain biology.
LRRTM4 has previously been associated with childhood aggression, autism spectrum disorders, and Tourette syndrome, but the mechanisms behind these links have remained unclear. By switching off the corresponding gene in zebrafish, the team was able to study its effects on behavior, brain chemistry, and gene expression. The results suggest that LRRTM4 may influence how threats are perceived and responded to, possibly by altering neurotransmitter systems such as dopamine and adenosine.
Florian Reichmann and his team at the Medical University of Graz were drawn to this line of research because of prior genetic studies linking LRRTM4 polymorphisms with aggression and neurodevelopmental disorders. While large genome-wide association studies have found correlations between variations in this gene and traits like aggression or autism, these studies do not reveal how the gene actually influences brain function.
“Our lab is very interested in behavioural neurogenetics to study the influence of genetic factors on behavior,” Reichmann told PsyPost.
LRRTM4 codes for a synaptic adhesion protein involved in shaping connections between neurons, especially in brain regions responsible for emotion and memory. Its role in organizing synaptic transmission makes it a promising candidate for investigating behavioral regulation. Despite this, no previous animal study had examined the behavioral consequences of knocking out LRRTM4 or its orthologues. Reichmann’s group aimed to close this gap using zebrafish, a model increasingly used in neuroscience due to their genetic similarity to humans and transparent, fast-developing embryos.
“When we started this work no detailed behavioral characterization in an animal model with disturbed Lrrtm4 function existed,” Reichmann explained. “We wanted to fill this gap by using zebrafish as a model system and try to understand the consequences of lrrtm4l1 deficiency, a zebrafish orthologue of the LRRTM4 gene, at the behavioral level.”
Zebrafish share about 70 percent of their genes with humans, and over 80 percent of disease-linked genes have a zebrafish equivalent. Their social nature, well-characterized behaviors, and ease of genetic manipulation make them well-suited for studying the neural and molecular basis of social traits.
The researchers began by mapping where the lrrtm4l1 gene was most active in the zebrafish brain. They found high expression in the telencephalon, inferior lobe, and optic tectum—regions associated with emotion regulation, sensory processing, and social decision-making. Notably, the gene was strongly expressed in the dorsal and medial zones of the telencephalon, which correspond to the hippocampus and amygdala in mammals. These structures are known to be involved in fear, memory, and threat detection.
Next, the researchers created a line of zebrafish with a disrupted version of the lrrtm4l1 gene. These mutant fish appeared physically normal, but their behavior differed significantly from that of wild-type fish. In multiple anxiety-related tests, the mutants showed signs of heightened nervousness. They moved less in open spaces, avoided the upper parts of a novel tank, and showed erratic swimming patterns—typical indicators of anxiety in zebrafish models.
In contrast, when tested for aggression using a mirror-based challenge, the mutant fish were less combative than their unaltered counterparts. They spent less time confronting their reflection, though they were just as quick to notice it. The researchers concluded that the lowered aggression was unlikely to be a side effect of anxiety alone. Importantly, other social behaviors such as shoaling and response to familiar versus unfamiliar groups were unaffected, suggesting that the gene specifically influences aggression without impairing social engagement more broadly.
“The most important findings are that zebrafish with lrrtm4l1 deficiency are more anxious and less aggressive,” Reichmann told PsyPost. “This suggests that the gene plays an important role for these behaviors.”
On a molecular level, deleting the gene caused widespread changes in brain activity. Transcriptomic analysis of the telencephalon revealed 126 genes that were either up- or down-regulated compared to controls. Many of these were involved in neural signaling and synaptic plasticity. For example, the researchers noted increased expression of genes involved in neurotransmitter regulation and reduced expression of genes linked to excitatory synapse function.
A particularly notable finding was increased dopamine turnover in the mutant fish. Dopamine is a neurotransmitter involved in reward, motivation, and aggression. The researchers found higher levels of homovanillic acid, a breakdown product of dopamine, suggesting faster dopamine metabolism. While dopamine itself was not elevated, the ratio of its metabolite to the original neurotransmitter pointed to a shift in how the brain was using this chemical.
The team also detected lower levels of adenosine, another neurotransmitter involved in regulating arousal and anxiety. Reduced adenosine has been linked to anxiety-like behavior in both fish and mammals. Additional changes were noted in serotonin and melatonin levels, though these did not reach statistical significance.
“Mechanistically, we found gene expression changes in the glutamatergic and serotonergic neurotransmitter systems as well as altered concentrations of homovanillinic acid, a dopamine metabolite and adenosine in the mutant brain, indicating strong effects on multiple major neurotransmitter systems,” Reichmann said.
In untargeted metabolomics, the researchers found reduced levels of a compound similar to methyl vanillate, a derivative of vanillic acid with reported antioxidant and neuroprotective properties. They also observed changes in molecules related to lipid metabolism and amino acid processing. These biochemical shifts add another layer of evidence that the gene influences brain function at multiple levels, from structural development to real-time neurotransmission.
Taken together, the findings suggest that lrrtm4l1 influences behavior by shaping how the brain responds to threats and social stimuli. The changes in neurotransmitter dynamics and synaptic signaling likely contribute to the behavioral differences seen in the mutant fish.
“The observed changes in the dopaminergic and serotonergic neurotransmitter system are surprising, because so far LRRTMs have been described as important regulators of excitatory glutamatergic synapses and inhibitory retinal GABAergic synapses only,” Reichmann explained. “This warrants further investigation. On the other hand our findings of reduced aggression in lrrtm4l1 mutants fits with the described association of aggression and LRRTM4 in humans.”
While the results provide new insight into how LRRTM4 may shape behavior, the authors caution against drawing direct conclusions about human conditions from zebrafish models. One limitation is that zebrafish have a second version of the LRRTM4 gene, known as lrrtm4l2, which was not examined in this study. It remains unclear whether this second gene compensates for the loss of lrrtm4l1 or has its own distinct role.
“This gene might have similar functions to lrrtm4l1, but also other functions/effects,” Reichmann said. “It would be interesting to study a double knockout mutant line for both of these genes.”
Another open question is whether the effects observed in zebrafish would be mirrored in mammals. “A next step could therefore also be to investigate the effects of Lrrtm4 deficiency on emotional-affective behaviour in another species such as the mouse,” Reichmann noted.
The study, “Deficiency of the Synaptic Adhesion Protein Leucine-Rich Repeat Transmembrane Protein 4 Like 1 Affects Anxiety and Aggression in Zebrafish,” was authored by Eva Tatzl, Giulia Petracco, Isabella Faimann, Marco Balasso, Agnes Anna Mooslechner, Thomas Bärnthaler, Giovanny Rodriguez-Blanco, and Florian Reichmann.
