News

Network Oscillations as a Model for CNS Drug Discovery

News

27.03.2025

Brain rhythms are periodic fluctuations of neuronal activity that emerge from the synchronized firing of large populations of neurons. These oscillations play a fundamental role in brain function, reflecting coordinated network activity across various cortical and subcortical regions.

Different brain rhythms are associated with specific behavioral states, neuronal mechanisms, and cognitive functions. Slow oscillations (<1 Hz), Delta (1-4 Hz) , Theta (4-12 Hz) , Beta (12-30 Hz), Gamma (20-80 Hz), Sharp wave ripples (150-250 Hz). Among these, gamma oscillations are particularly relevant for CNS drug discovery, as they are often disrupted in disorders such as schizophrenia, Alzheimer’s disease, and depression.

The Role of the Hippocampus

The Hippocampus is a key structure involved in generating large local field potentials, particularly in the CA3 and CA1 regions. The dense arrangement of pyramidal cell dendrites enables synaptic currents to sum together, producing large rhythmic signals easily detected in electrophysiological recordings. The hippocampus exhibits multiple oscillatory activities: Theta oscillations (4-12 Hz), occurring during active exploration and REM sleep; Gamma oscillations (20-80 Hz), associated with cognitive functions such as attention and memory; Sharp wave ripples (150-250 Hz), which facilitate memory consolidation by replaying previous activity in a temporally compressed manner during slow-wave sleep and waking immobility.

Mechanisms of Gamma Oscillations

Gamma oscillations emerge from reciprocal interactions between excitatory pyramidal cells and inhibitory interneurons, particularly parvalbumin-positive basket cells, which synchronize pyramidal neuron activity through rhythmic inhibition.

Two well-characterized in vitro models for studying hippocampal oscillations:

Carbachol-induced oscillations: Mimic cholinergic input from the septum, generating alternating cycles of AMPA receptor-mediated excitation followed by feedback inhibition from perisomatic-targeting interneurons.
Kainate-induced oscillations: Provide tonic excitation via ionotropic glutamate receptor activation, affecting both excitatory and inhibitory neurons.
In vivo studies have demonstrated that ketamine and MK-801 enhance the power of cortical gamma oscillations in both rodents and humans (Hakami et al., 2009; Kocsis et al., 2012; Hiyoshi et al., 2014; Shaw AD et al., 2015). In vitro data from Neuroservice revealed that from 10 µM, ketamine increases power in the beta range, driven by a shift of gamma oscillation toward lower frequencies.

Other tested drugs (data not shown):

Antipsychotic drugs: In vitro, data from Neuroservice reveal that clozapine and haloperidol reduce the power of kainate-induced oscillations. Similarly, in vivo studies have shown that both clozapine and haloperidol reduce the power of cortical gamma oscillations or reverse the increase in gamma power induced by NMDA receptor antagonists (Hudson MR et al., 2012) (Schulz SB et al., 2012).
Serotonin: In vitro, 5-HT and mCPBG—a 5-HT3 agonist—reduce gamma oscillations (Neuroservice data), consistent with in vivo findings in the prefrontal cortex (Puig, 2010).
Norepinephrine decreases gamma oscillations while increasing frequency, both in vitro (Neuroservices- Alliance data) and in vivo in the hippocampus (Brown et al., 2005).
Opioids: Fentanyl impaired network oscillations.
Neuregulin-ERBb4 pathway: NRG-1β – an epidermal growth factor receptor (EGFR) agonist – increases the power and decreases the frequency of kainate-induced oscillations.
Tetraethylammonium (TEA) – an inhibitor of Ca2+-activated K+ (SK) channels – significantly increases the magnitude of network oscillations and reduces their frequency.