Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation.

Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition.

α5 subunit-containing GABA type-A receptors (α5 GABARs) are enriched in the hippocampus and play critical roles in neurodevelopment, synaptic plasticity, and cognition. α5 GABAR preferring negative allosteric modulators (α5 NAMs) show promise mitigating cognitive impairment in preclinical studies of conditions characterized by excess GABAergic inhibition, including Down syndrome and memory deficits post-anesthesia. However, previous studies have primarily focused on acute application or single-dose α5 NAM treatment.

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms.

Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more "holistic" understanding of synaptic interplay.

Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission.

α5 subunit GABA type A receptor (GABAR) preferring negative allosteric modulators (NAMs) are cognitive enhancers with antidepressant-like effects. α5-NAM success in treating mouse models of neurodevelopmental disorders with excessive inhibition have led to Phase 2 clinical trials for Down syndrome. Despite in vivo efficacy, no study has examined the effects of continued α5-NAM treatment on inhibitory and excitatory synapse plasticity to identify mechanisms of action.

Anterograde trafficking signals in GABA subunits are required for functional expression.

Pentameric GABA receptors are composed from 19 possible subunits. The GABA β subunit is unique because the β and β subunits can assemble and traffic to the cell surface as homomers, whereas most of the other subunits, including β, are heteromers. The intracellular domain (ICD) of the GABA subunits has been implicated in targeting and clustering GABA receptors at the plasma membrane.