Understanding complex brain functions by studying a rare brain disease
Understanding complex brain functions by studying a rare brain disease
10 October 2025
How the human brain learns and stores memories is among the most intricate capabilities of the human brain, and plays an essential role in everyday life. The molecular and cellular mechanisms underlying these complex features remain insufficiently understood. A collaborative research team from the Institute of Molecular and Cellular Physiology (IBI-1) and the Institute of Neuroscience and Medicine (INM-10) at the Forschungszentrum Jülich has obtained novel insights by stuying a rare human genetic condition linked to intellectual disability and epilepsy.
The image illustrates a comparison between hippocampal tissues from ClC-3-deficient (upper left) and wild-type conditions (healthy). In the ClC-3-deficient hippocampus, neuronal cells display markedly reduced structural complexity, with fewer and less elaborate dendritic branches compared to normal neurons. By visualizing these structural changes, the image provides direct evidence of how disruptions in ClC-3 function can alter the cellular architecture of the hippocampus. | Credits: Forschungszentrum Jülich / edited with ChatGPT
Scientific Focus of the Study
The researchers focused on two chloride/proton exchangers – the protein ClC-3 and ClC-4 – which play an essential role in cognition. They are particularly active in regions critical for cognition, such as the hippocampus and thalamus – brain regions crucial for learning and information processing. These proteins are primarily located in the endo/lysosomal system, a network of small vesicles involved in intracellular transport, recycling, and degradation. This system ensures that molecules are properly sorted and broken down – essentially the cell’s “recycling center.” Within this system, chloride/proton exchangers make a major contribution to cellular homoeostasis – that is, the cell’s internal balance – by maintaining proper pH levels, electrical charge distribution, and the functional integrity of subcellular compartments. However, the precise mechanisms by which chloride/proton exchangers regulate these processes have long remained elusive.
Mutations in the genes encoding ClC-3 and ClC-4, CLCN3 and CLCN4, cause a broad range of neurological and neuropsychiatric complications. Collectively known as CLCN3- and CLCN4-related neurodevelopmental disorders, affected individuals often face challenges with learning, reasoning, and problem-solving (intellectual disability). Many also experience global developmental delay, which affects skills such as movement, speech, and social interaction. In addition, seizures that do not respond well to available medications (drug-resistant epilepsy) are common and can severely impact the quality of life. Currently, there are no targeted treatments for these disorders. Care is mainly limited to managing symptoms with general medications or supportive therapies, such as speech, physical, or occupational therapy. This lack of effective options highlights the urgent need for novel and effective therapeutic strategies.
Using electrophysiological recordings (to measure neuronal electrical activity) and high-resolution cellular imaging on acute brain slices from animal models of the disease, the Jülich researchers discovered a link between ClC-3/ClC-4 activity, neuronal excitability and morphology. They found that these chloride/proton exchangers regulate the number of a particular class of potassium channels (Kv7/KCNQ) in the neuronal membrane. These channels determine how easily a neuron generates an electrical signal – an action potential – effectively acting as a “dial” for neuronal excitability. When functional ClC-3 or ClC-4 transporters are missing, the density of potassium channels at the cell surface changes. This disturbs the electrical balance within the neuron, making it more likely to fire irregularly or too easily. Such dysregulation could underlie both epileptic seizures and cognitive impairments observed in affected individuals.
A potential therapeutic approach
Using these insights, the Jülich team proposed a potential therapeutic approach, demonstrating that blocking Kv7/KCNQ channels can restore near-normal electrical activity in neurons lacking functional CLC transporters.
Significance of the findings
Their finding not only advances our fundamental understanding of how intracellular ion exchangers shape neuronal signaling and influence brain function but also identifies a promising therapeutic target for treating CLCN3/4-related neurodevelopmental conditions.
The cartoon illustrates the proposed underlying mechanisms linking chloride/proton exchangers to neuronal excitability. Under normal conditions, these exchangers regulate the density of Kv7/KCNQ potassium channels at the neuronal membrane. By influencing how many of these channels are available, ClC-3 and ClC-4 help indirectly to set the threshold for neuronal firing and stabilize the patterns of electrical activity that neurons use to communicate. When chloride/proton exchangers fail, the balance is disturbed, making neurons more prone to abnormal firing patterns. This disruption of electrical signaling might thus contribute to the seizures and cognitive impairments observed in CLCN3/4-related disorders. The cartoon also illustrates a potential therapeutic strategy. Pharmacological modulation of Kv7/KCNQ channels can restore neuronal electrical activity even in the absence of fully functional CLC exchangers. By adjusting the activity of these potassium channels, the abnormal excitability caused by exchanger dysfunction can be counterbalanced, allowing neurons to fire in a more controlled and physiologically normal manner. | Credits: Forschungszentrum Jülich
Original Publication
Qi et al., 2025, Brain, https://doi.org/10.1093/brain/awaf243
