How does the neurotransmitter GABA produce myriad forms of inhibition in the central nervous system (CNS), restraining and shaping electrical activity to prevent anxiety, agitation, seizures, chronic pain and sleep disturbance?
How does GABAergic dysfunction impair early brain circuit development and contribute to neurodevelopmental disorders?
The majority of fast synaptic inhibition in the CNS is mediated by GABA type A neurotransmitter receptors (GABAARs) which are chloride (Cl-) selective ligand-gated ion channels composed of five subunits (from up to 19 unique subunits in humans), with differential expression across brain regions, cell types and subcellular localization. The Jacob lab’s broad goal is to identify molecular mechanisms regulating dynamic GABAAR inhibition and understand how this impacts neurodevelopment and synaptic plasticity and is modified by drug treatment and pathological conditions. We use a combination of biochemical, pharmacological, functional and imaging based approaches.
Benzodiazepine induced neuroplasticity
GABAAR are the sites of action of many clinically important drugs, including the benzodiazepines (BZs), which are front line treatments for anxiety, insomnia, schizophrenia and epilepsy. Although effective, BZ use is limited by the development of tolerance, dependence, and withdrawal. The Jacob lab is investigating modulation of GABAAR trafficking and inhibition by BZs and other GABAAR targeted drugs. More broadly, we are applying biochemical, proteomic, novel optical methods and electrophysiological approaches to identify neuroadaptations induced by BZ treatment both at excitatory and inhibitory synapses.
Significance: Knowledge generated by these studies will advance therapies to treat BZ tolerance.
GABA A receptor subtype regulation of brain circuit formation
Many neurodevelopmental disorders including autism, intellectual disability, and childhood epilepsy syndromes share a common cause – dysfunction in GABAergic neurotransmission. Mutations in GABAAR subunits and other imbalances in the ratio of excitatory/inhibitory neuronal signaling produce these pathologies. The majority of excitatory synapses in the brain are located at the end of dendritic spines, small protrusions from neuronal processes, with neighboring GABAergic synapses predominantly located on dendritic shafts but also found on dendritic spines. Importantly, GABAAR subunit composition largely defines receptor localization, interacting proteins, electrophysiological properties and drug sensitivities. The Jacob lab is investigating GABAAR subtype specific mechanisms regulating early neuronal development and circuit formation.
Significance: This research will improve understanding of how GABAergic dysfunction contributes to neurodevelopmental disorders.