Olanzapine is an atypical antipsychotic that is reported to be effective without producing the disabling extrapyramidal side effects associated with the older, typical antipsychotic drugs (Duggan et al., 2003). The effects of olanzapine on the Electroencephalogram (EEG) in patients with schizophrenia include inducing EEG slowing less frequently (in 44% of the patients) (Schuld et al., 2000). Olanzapine is an antagonist of muscarinic receptors; serotonin receptors; histamine H1 receptors; dopamine receptors and adrenergic alpha-1 receptors. Serotonin and dopamine receptors participate in the process of gamma oscillations. Serotonin suppresses the power of gamma oscillations (Wojtowicz et al., 2009). Gamma oscillations are thought to temporally link the activity of distributed neurons. Memory encoding and retrieval are coordinated by different frequencies of hippocampal gamma oscillations. In the hippocampus, a brain region critically involved in storage, encoding, and retrieval of memory (Squire et al., 2004). Theta and gamma rhythms in the hippocampus, and their distinctive temporal properties fit well with different coordinated brain functions. Gamma oscillations have been observed to be altered in many psychiatric disorders, such as schizophrenia and bipolar disorder (Sohal, 2022). In schizophrenia, both parvalbumin interneuron function and task-induced gamma oscillations are deficient (Sohal, 2022). Olanzapine is a thienobenzodiazepine classified as an atypical or second-generation antipsychotic agent. How olanzapine modulates gamma oscillation power needs to be further explored.

In hippocampal slices gamma oscillations can be induced by pharmacological activation of muscarinic receptors (Fisahn et al., 1998a), group I metabotropic glutamate receptors (Whittington et al., 1995) or kainate receptors (KARs) (Hormuzdi et al., 2001). As an antagonist of muscarinic receptors, olanzapine may affect gamma oscillations in the hippocampus. Gamma oscillations (30

80 Hz) are observed in many brain regions and most prominently in the hippocampus (Bragin et al., 1995). The synchronous discharges of excitatory neurons and inhibitory interneurons constitute gamma oscillation, which are recruited during a variety of cognitive tasks such as memory and cognition (Buzsaki and Wang, 2012; Howard et al., 2003).

The prefrontal cortex (the frontal association area, FrA) is implicated in associative learning. The hippocampus and the prefrontal cortex are highly innervated by serotonergic afferents originating in the midbrain raphe nuclei (Groenewegen and Uylings, 2000; Hensler JG, 2006) and express serotonin 5-HT1A and 5-HT2A receptors (Celada et al., 2013). The reset of hippocampal-prefrontal circuitry has been shown to facilitate learning (Park et al., 2021). Hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways (Brockmann et al., 2011). The theta rhythm, characterized by its large amplitude and relatively slow, highly regular frequency of 4–12 Hz, plays a crucial role in spatial memory processing. It's noteworthy that olanzapine is an antagonist of muscarinic receptors, serotonin receptors, and dopamine receptors. How does olanzapine affect theta and gamma oscillatory activity in the prefrontal cortex and hippocampus? To address the question, we recorded local field potentials from the prefrontal cortex in vivo and hippocampal slices. Olanzapine's modulation of local field potentials in the hippocampal CA3 region and the prefrontal cortex likely contributes to its pharmacological action.