P/Q-type calcium channels, also known as CaV2.1, are voltage-gated Ca2+ channels (VGCCs) enriched at many central synapses where they control neurotransmitter release. Loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of CaV2.1, underlie several neurological disorders, including episodic ataxia type II (EA2) and absence epilepsy.Despite the existence of several experimental models, the etiology of these diseases still remains poorly understood, preventing the development of effective therapeutic strategies.Here, we have developed a CRISPR/Cas9-mediated strategy to generate a new mouse model of episodic ataxia and absence epilepsy by selectively knocking down CaV2.1 expression in pyramidal neurons of the forebrain. By combining EEG recordings, optogenetics, electrophysiological and behavioral studies, we showed that the reduction of CaV2.1 cortical levels alters AMPA and GABAergic transmissions, induces sensorimotor dysfunctions and increases seizure susceptibility.Moreover, characterization of human iPSC-induced neurons carrying two different CACNA1A loss-of-function mutations associated with EA2 revealed two different phenotypes. While the missense mutation F1491S severely impairs neuronal induction and differentiation, iPSCs carrying the truncating mutation Y1854X are able to properly differentiate but display reduced neuronal activity and impaired synaptic communication.Altogether, these new experimental models will allow for testing new therapeutic approaches suitable for all CACNA1A loss-of-function mutations.