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Intriguingly, these synaptic perturbations coexisted with increased non-synaptically driven activity, as characterized by inhibition of N-methyl-D-aspartate and AMPA receptors on micro-electrode arrays. Single-cell electrophysiology and gene expression analysis corroborated this increased intrinsic excitability through reduced potassium channel function and expression. Moreover, we observed partial mitigation of the CACNA1A+\/\u2212 network phenotype by 4-aminopyridine, a therapeutic intervention for episodic ataxia type 2. Positive modulation of small conductance calcium-activated potassium channels could reverse the CACNA1A+\/\u2212 network electrophysiological phenotype.<\/jats:p>\n               <jats:p>In summary, our study pioneers the characterization of a human induced pluripotent stem cell-derived neuronal model for CACNA1A haploinsufficiency and has unveiled new mechanistic insights. Beyond showcasing synaptic deficits, this neuronal model exhibited increased intrinsic excitability mediated by diminished potassium channel function, underscoring its potential as a therapeutic discovery platform with predictive validity.<\/jats:p>","DOI":"10.1093\/brain\/awae330","type":"journal-article","created":{"date-parts":[[2024,10,26]],"date-time":"2024-10-26T16:23:52Z","timestamp":1729959832000},"page":"1286-1301","source":"Crossref","is-referenced-by-count":21,"title":["<i>CACNA1A<\/i> haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3238-9693","authenticated-orcid":false,"given":"Marina P","family":"Hommersom","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour , Nijmegen 6500 HB ,","place":["The 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