SUMMARY: UCLA researchers in the Department of Neurology have developed a novel small molecule to improve native gamma oscillations as a treatment for cognitive decline in various neurological disorders. BACKGROUND: Neural circuits are facilitated by brain oscillations or rhythmic electric activity at distinct frequencies. These frequency variations are critical for correctly linking together circuits of neurons in the central nervous system. These oscillatory activities are dependent on precise inhibitory-excitatory neuronal interactions. Oscillations at the frequency 30-120 Hz, also known as γ-oscillations, are known to organize the neuronal circuits critical for learning and memory. Importantly, numerous studies also characterize reduction of γ-oscillations in many neurological and psychiatric disorders, such as early cognitive decline in Alzheimer’s disease . Recent evidence suggests that stimulating brain frequencies in mouse models of Alzheimer’s diseases is able to alleviate disease pathology. However, such approaches are not feasible in human cases of cognitive impairment due to the required duration of stimulation, lack of access to all brain regions, and misalignment with native brain oscillations. In humans, the generation of γ-oscillations is regulated by the brain’s parvalbumin (PV) expressing interneurons (PV+INs) that uniquely express γ-aminobutyric acid type A receptors (GABAARs). GABAARs from interneurons have been shown to powerfully regulate the dynamics of γ-oscillations. Thus, these receptors are ideal therapeutic targets to selectively increase γ-oscillations throughout the brain. GABAARs, however, have been shown to be insensitive to benzodiazepines, popular small molecule drugs targeting brain activity. To effectively target these receptors as a means to treat cognitive impairment from neurological disorders, a novel class of small molecules must be designed. INNOVATION: Researchers at UCLA from Dr. Istvan Mody’s group have proposed the use of small molecule new chemical entities (NCEs) to inhibit GABAARs. NCEs will increase γ-oscillations by reducing the tonic inhibition of PV+INs. Unlike cranial stimulation, this approach will amplify naturally occurring γ-oscillations through activity of PV+INs resulting in improved cognitive function. Dr. Mody’s research has validated this concept by identifying small molecules that reduce receptor expression and increase γ-oscillations. Conversely, they identified that positive modulators decrease oscillations. Using EEGs on hippocampal slices, lead drug candidates have been identified to increase γ-oscillations by engaging GABAARs. These novel brain permeable NAMs will have profound change in the underlying cognitive impairments found in various neurological and psychiatric disorders. POTENTIAL APPLICATIONS: • Treatment to improve cognitive function in patients with Alzheimer’s, Schizophrenia, epilepsy, and others • Improve on brain stimulation-based treatments ADVANTAGES: • Modulates native brain oscillations • Improved bioavailability of treatment to the all regions of the brain • Increased specificity to only neurons that modulate γ-oscillations DEVELOPMENT-TO-DATE: Proof of concept in laboratory settings has been established. Lead drug candidate show increase in γ-oscillations in hippocampal slices. Related Papers (from the inventors only) Barth, A.M., Ferando, I. and Mody, I. (2014) Ovarian cycle-linked plasticity of delta-GABAA receptor subunits in hippocampal interneurons affects gamma oscillations in vivo. Frontiers in cellular neuroscience 8, 222 Ferando, I. and Mody, I. (2015) In vitro gamma oscillations following partial and complete ablation of delta subunit-containing GABAA receptors from parvalbumin interneurons. Neuropharmacology 88, 91-98,