A groundbreaking study has shed light on how a seldom-seen genetic anomaly can disrupt brain cell interactions, offering vital understanding of its role in a major neurological condition called developmental and epileptic encephalopathy (DEE). Insights from the research show that a mutation in a regulatory calcium channel component interferes with the calcium processing and the structural connections integral to brain cells. This expands our knowledge on the genesis of specific neurological disorders. Conducted by a team at the Karl Landsteiner University of Health Sciences (KL Krems), the study’s findings are now available in the Journal of Neurochemistry.
Ion channels are essential for nerve signal transmission, necessitating precise functional control. The a2d protein family (pronounced “alpha-two-delta”) is pivotal in this regulation. As crucial regulatory units of voltage-gated calcium channels, these proteins have long been recognized for modulating calcium currents, a fundamental process for neuron activity and electrical signal processing. Recent discoveries also underscore a2d-2’s role in organizing the intricate connections, or synapses, between neurons. Researchers at KL Krems are honing in on a mutation in the CACNA2D2 gene that codes for a2d-2.
In their analysis of the p.R593P mutation found in two DEE-diagnosed siblings, scientists illustrated the mutation’s dual impact on both calcium management and neuronal structure. “Our findings elucidate how this mutation disrupts the essential balance between calcium channels and synapse organization, which are indispensable for typical brain operations,” notes Prof. Dr. Gerald Obermair, leading the Division of Physiology at KL Krems’ Department of Pharmacology, Physiology, and Microbiology. “These disruptions deliver vital insights not only on DEE but potentially more extensive neurodevelopmental and neuropsychiatric conditions linked to a2d proteins.”
Employing a mouse model with the human p.R593P equivalent, p.R596P, researchers observed its effects on hippocampal neurons, crucial for memory and learning. They found the mutation significantly diminishes a2d-2’s presence on the surface and synapses, which disturbs various aspects of neural connectivity. These alterations result in uneven synaptic calcium channel distribution and signaling molecule imbalances, hampering synaptic communication.
The mutation induces three specific synaptic functional changes. It disrupts the recruitment of postsynaptic GABAA receptors, crucial for inhibitory signaling, triggering excessive neuron activity, a hallmark of seizure disorders like DEE. Additionally, it influences the synapsin protein cluster essential for presynaptic structure in excitatory synapses. Lastly, there’s a recorded decline in miniature postsynaptic current amplitude, indicating weakened synaptic strength.
“These findings highlight the significance of a single gene mutation’s extensive influence, affecting brain connectivity and potentially inciting widespread brain function changes,” clarifies Sabrin Haddad, M.Sc., the study’s leading author and a PhD candidate with Prof. Obermair’s team at KL Krems. “The disruption in signaling pathways and synaptic architecture gives insight into the severe neurological symptoms seen in DEE cases.”
This detection of multifaceted impacts on both channel-related and synaptic functionalities underscores the urgency for “synaptopathies” research, conditions derived from impaired neuronal connections. By pinpointing these detailed molecular aspects, this investigation expands our comprehension of brain connectivity and evolution, paving potential paths for treatments to enhance synaptic connectivity and brain operations.
Original publication: A biallelic mutation in CACNA2D2 associated with developmental and epileptic encephalopathy affects calcium channel-dependent as well as synaptic functions of a2d-2. S. Haddad, C. Ablinger, R. Stanika, M. Hessenberger, M. Campiglio, N. J. Ortner, P. Tuluc, G. J. Obermair. Journal of Neurochemistry. 2024;00:1–24.
The Karl Landsteiner University of Health Sciences (KL Krems) is noted across Europe for its comprehensive education and research initiatives on the Campus Krems, offering advanced study program in medicine, psychology, and a PhD in mental health and neuroscience.