CaMKIIβ insufficiency disrupts cortical networks, producing aberrant low-gamma oscillations and seizure...

Pathogenic variants in the calcium/calmodulin-dependent protein kinase II B gene (CAMK2B) have been associated with neurodevelopmental disorders, including epilepsy, yet the mechanisms underlying cortical dysfunction remain largely unclear. Building on our previous clinical report of a patient carrying the CaMKIIβ P213L variant and our prior characterization of the corresponding mouse models, we investigated how P213L-associated CaMKIIβ insufficiency alters cortical network dynamics and susceptibility to pentylenetetrazol (PTZ)-induced seizures in vivo.

We performed electroencephalographic recordings for CaMKIIβ P213L knock-in mice under baseline and pharmacological modulation. Susceptibility to seizure induction by the chemoconvulsant PTZ was assessed. Cortical CaMKIIβ expression and Thr287 phosphorylation levels were quantified and compared to those in CaMKIIβ knockout mice.

Heterozygous and homozygous knock-in mice exhibited aberrant low-gamma (20-50 Hz) oscillations during resting state with behavioral immobility. These aberrant low-gamma oscillations were sensitive to γ-aminobutyric acid (GABA)-ergic modulation: pentylenetetrazol (PTZ) induced a downward shift in the gamma-band peak frequency, whereas isoflurane, diazepam, and valproic acid suppressed the aberrant low-gamma oscillations. PTZ administration increased seizure severity in both heterozygous and homozygous knock-in mice, but lethality occurred only in homozygous mice. We quantified cortical CaMKIIβ expression and Thr287 phosphorylation, both of which were reduced in knock-in mice. Knockout mice recapitulated the aberrant low-gamma oscillations and their pharmacological modulation observed in knock-in mice, supporting the role of CaMKIIβ insufficiency in driving the phenotype.

These findings suggest that CaMKIIβ insufficiency disrupts cortical excitatory-inhibitory balance, leading to the aberrant low-gamma oscillations and increased seizure susceptibility. Our findings establish a mechanistic link between CaMKIIβ deficiency and epilepsy-related phenotypes in neurodevelopmental disorders. The P213L variant represents a loss-of-function variant with reduced CaMKIIβ expression and phosphorylation, and provides a valuable model for investigating disease mechanisms and developing potential therapeutic strategies.