Mouse Model Helps Researchers Identify Processes Underlying Batten Disease Symptoms

Researchers found, in a new mouse model for Batten disease, that defective synapses in specific brain regions may be the cause of disease symptoms.

The study “Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis,” was published in the journal eLIFE.

Batten disease is caused by mutations (errors) in the CLN3 gene, leading to dysfunction of nerve cells and premature death. But how the mutations in the CLN3 gene induce the neurological symptoms that characterize the disease has not been fully understood.

Researchers at the Jena University Hospital in Jena, Germany, and colleagues at other institutions studied a mouse model for Batten disease – referred to as the Cln3^Δex1-6 mouse model – that was genetically engineered to lack the CLN3 gene. These are commonly known as knockout mice in the laboratory.

They then evaluated the functional and morphological changes that occurred in the central nervous system of the mice.

Researchers observed that the mice had increased anxiety-related behavior and reduced learning abilities, two symptoms in agreement with a lack of CLN3 protein. This protein is localized in isolated nerve terminals, and it causes defects in synaptic transmission. Synapses allow the transmission of nerve impulses from one neuron to the next.

The mice also showed a marked loss of GABAergic interneurons – neurons that release the neurotransmitter gamma-aminobutyric acid, or GABA – in two specific brain regions, the amygdala and hippocampus.

They investigated the motor function of these mice, since motor dysfunction is also one of the symptoms in these patients, including bradykinesia (slowness of movement) and ataxia (lack of voluntary coordination of muscle movements). Ultimately, patients lose their ability to walk.

The CLN3 knockout mice also showed motor deficits, noticeable at 7 months of age and continuing to progress until they were 14 months old. At this age, the mice’s walking ability was impaired, as shown by their performance in the accelerating RotaRod test and walking distance.

Since movement coordination is mainly controlled by cerebellar function, these findings suggest that the motor deficits and ataxia are the result of impaired signaling in the cerebellum.

“We found that synaptic transmission is severely disturbed in the amygdala, hippocampus, and cerebellum, accounting for progressive disease signs in the Cln3^Δex1-6 mouse model,” researchers wrote.

The researchers noted that this dysfunction is likely mediated by the loss of certain GABAergic interneurons in the affected brain regions.

Patients with Batten disease, as well as the CLN3 knockout mice, were previously shown to carry autoantibodies against GAD65, a protein involved in the production of the GABBA neurotransmitter.

“Considering the specific loss of certain subtypes of interneurons shown here, the role of anti-GAD65 specific autoantibodies and T-cell reactivity to GAD65 should be investigated also in Batten disease,” the study concluded.