CARIPRAZINE ALTERS INTRINSIC EXCITABILITY AND NETWORK DYNAMICS OF MOUSE HIPPOCAMPAL NEURONS IN A CELL TYPE-DEPENDENT MANNER

Schizophrenia is a severe psychiatric disorder characterized by a heterogeneous set of symptoms. Effective therapeutical management requires agents that attenuate multiple symptom domains, while maintaining acceptable tolerability. Cariprazine is a third-generation antipsychotic drug acting on dopamine D2/D3 receptors and has demonstrated its efficacy in reducing both positive and negative symptoms. In this study, we investigated the effects of cariprazine on neuronal physiological properties and network activity using primary hippocampal cultures from mice, employing whole-cell patch-clamp and multielectrode array (MEA) measurements. Our patch-clamp experiments revealed that acute treatment with 1 μM cariprazine induced a shift in the firing phenotypes of hippocampal neurons, with regular firing type cells tending to adopt an irregular/stuttering firing mode in the presence of the drug. This effect was more pronounced in neurons exhibiting strong, D-type voltage-dependent K-currents, which are known to contribute to the generation of irregular firing patterns in several neuronal cell types, including interneurons. Consistent with these findings, MEA recordings demonstrated that acute treatment with cariprazine reduced overall network activity in hippocampal cultures, an effect comparable to that observed with other antipsychotics. Lastly, we utilized computational modeling to simulate cariprazine-induced upregulation of the D-type K-current and to study its effect on intrinsic excitability and firing regularity. Results from the model simulations provided a more refined interpretation of the data on excitability and firing responses. Collectively, these results complement existing literature on the favorable pharmacological profile of cariprazine and provide new insights into the cellular and network-level mechanisms underlying its therapeutic actions.