The effects of AUT00206, a novel Kv3.1/3.2 potassium channel modulator, on task-based reward system activation: a test of mechanism in schizophrenia

Journal article

Schizophrenia is a debilitating neurodevelopmental disorder, with current antipsychotic drugs facing challenges due to incomplete understanding of its aetiopathophysiology. The cerebellum is involved in all brain functions, including higher cognitive functions, with cerebellar dysfunction seen to play an important role in schizophrenia. The Kv3 voltage-gated potassium channels (Kv3.1–Kv3.4) are critical for fast neuronal firing and show distinct yet overlapping expression patterns in the cerebellum. While Kv3.1 reduction has been observed in the cerebral cortex of schizophrenia patients and animal models, there are no studies investigating Kv3.3 and Kv3.4 in schizophrenia. This project used a subchronic phencyclidine (PCP) mouse model to assess changes in cerebellum-related behaviour, cerebellar morphology, and Kv3 channel expression. Various techniques were used including PCP model generation, rodent behaviour analysis, transcardiac perfusion, brain dissection and vibratomy, immunohistochemistry and confocal imaging, and western blot. Behavioural analysis revealed impairments in motor coordination and balance in the PCP group, shown by deficits in horizontal bar and vertical pole tests. There was no change in the gross anatomy of the cerebellum in the PCP mouse model, with the molecular and granule layer thickness remaining unchanged. The Purkinje cell linear density and granule cell size also remained unchanged, however, there was a significant decrease in the Purkinje size and granule cell density compared to the control group. The expression of Kv3.1b and Kv3.3 were both seen to be significantly downregulated in the cerebellum from the PCP group; while Kv3.1b was downregulated in the molecular layer of the hemispheres, Kv3.3 reduction was restricted to the molecular layer and Purkinje cell layer of the vermis. Kv3.4 expression remained unchanged in the PCP group. In conclusion, subchronic PCP exposure led to specific structural and molecular changes in the cerebellum, particularly affecting Purkinje cell morphology and Kv3.1b/Kv3.3 expression in distinct cerebellar regions. These alterations may contribute to the motor deficits and cerebellar dysfunction associated with schizophrenia. Future studies will investigate morphological changes in fine structures, such as Purkinje cell dendrites, and assess the potential therapeutic reversal effects of Kv3 positive modulators, with larger sample sizes to improve statistical power and reliability

Authors: Kaar, SJ; Angelescu, I; Nour, MM; Marques, TR; Sharman, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: Psychopharmacology
• Volume: 239
• Issue: 10
• Pages: 3313-3323
• Publication date: 2022-09-12
• DOI: 10.1007/s00213-022-06216-3
• EISSN: 1432-2072
• ISSN: 0033-3158
• Language: English
• Keywords: Inhibitory postsynaptic potential; Schizophrenia (object-oriented programming); Psychiatry; Functional magnetic resonance imaging; Anticipation (artificial intelligence); Dopaminergic; Ventral striatum; Associative learning; Dopamine; GABAergic; Neuroscience; Striatum; Psychology