Abstract
The diversity of inhibitory interneurons allows for the coordination and modulation of excitatory principal cell firing. Interneurons that release GABA (γ-aminobutyric acid) onto the soma and axon exert powerful control by virtue of proximity to the site of action potential generation at the axon initial segment (AIS). Here, we review and examine the cellular and molecular regulation of soma and axon targeting GABAergic synapses in the cortex and hippocampus. We also describe their role in controlling network activity in normal and pathological states. Recent studies have demonstrated a specific role for postsynaptic dystroglycan in the formation and maintenance of cholecystokinin positive basket cell terminals contacting the soma, and postsynaptic collybistin in parvalbumin positive chandelier cell contacts onto the AIS. Unique presynaptic molecular contributors, LGI2 and FGF13, expressed in parvalbumin positive basket cells and chandelier cells, respectively, have also recently been identified. Mutations in the genes encoding proteins critical for somatic and AIS inhibitory synapses have been associated with human disorders of the nervous system. Dystroglycan dysfunction in some congenital muscular dystrophies is associated with developmental brain malformations, intellectual disability, and rare epilepsy. Collybistin dysfunction has been linked to hyperekplexia, epilepsy, intellectual disability, and developmental disorders. Both LGI2 and FGF13 mutations are implicated in syndromes with epilepsy as a component. Advancing our understanding of the powerful roles of somatic and axonic GABAergic contacts in controlling activity patterns in the cortex and hippocampus will provide insight into the pathogenesis of epilepsy and other nervous system disorders.
Highlights
The functional output of the nervous system relies upon coordinated patterns of activity within neuronal circuitry
Some of the postsynaptic specialization of GABAA receptors (GABAARs) is conferred by the α subunit, with α1 containing receptors enriched on the dendrites and soma, and α2 containing receptors enriched on the soma and axon initial segment (AIS) (Jacob et al, 2008)
The modulation of excitatory pyramidal cells by GABAergic interneurons is determined by interneuron diversity, allowing for the complex computations performed by these neuronal circuits (Tremblay et al, 2016)
Summary
The functional output of the nervous system relies upon coordinated patterns of activity within neuronal circuitry. Neuronal circuits in the cortex and hippocampus are composed of excitatory pyramidal cells, but a multitude of diverse interneuron types that express unique complements of proteins and play distinct functional. Further complexity is added due to brain circuits likely relying on unique mechanisms to control synapse targeting, specificity, and molecular specialization. We examine the cellular and molecular regulation of soma and axon targeting GABAergic synapses in the cortex and hippocampus, as well as clarify their role in controlling network activity in these respective circuits. Because unique mechanisms likely exist in each circuit, we will compare and contrast soma and axon targeting GABAergic synapses in the cortex and hippocampus based on current research. We examine the role of soma and axon targeting GABAergic synapse dysfunction in pathological states, linking animal phenotypes and human syndromes to key molecular contributors at soma and axon targeting synapses of cortical and hippocampal circuits
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