Fast ionotropic inhibitory neurotransmission, mediated by presynaptic GABAergic terminals and correctly positioned postsynaptic GABAA receptors (GABAARs), occurs in about 30–40% of all synapses in the CNS. However, little is known about the specific control mechanisms responsible for patterned expression, assembly, trafficking, and targeting of GABAA receptors to GABAergic synapses or extrasynaptic domains within a single neuron. In this study, a cultured hippocampal neuron (CHN) model was used to examine the distribution and patterning of 13 different GABAAR subunit isoforms from 4 distinct subunit classes normally expressed in the brain. The group of experiments in this thesis shows that CHNs, as in the intact hippocampus, express and postsynaptically concentrate (cluster) GABA AR subtypes containing the α1–3, α 5, Î21–3, Î32S, Î32L and Î3 3 subunit isoforms. This postsynaptic clustering of GABAARs in CHNs primarily occurs apposed to inhibitory presynaptic contact and contains receptors with the Î32 or Î33 subunit. However, when presynaptic GABAergic terminals are absent from the local dendritic environment, significant GABAAR clustering occurs apposed to excitatory synaptic contact forming â€mismatched’ synapses. GABAAR clustering is particularly pronounced within the synapses onto the axon initial segment (AIS) of pyramidal cells in the brain, a phenomenon that also occurs in the AIS of CHNs independently of GABAergic or glutamatergic terminal phenotype. However, the coexistence of two different terminal phenotypes does not seem possible within this subcellular structure, due to the hierarchy of organizational signals created by correctly matched GABAergic synapses vs. mismatched synapses. Thus, we show that competition between GABAergic and glutamatergic terminals ultimately determines the postsynaptic localization of the GABAAR subtypes with a capacity for clustering. Lastly, this work addressed a molecular mechanism of GABAAR clustering. CHNs, as in the brain, are capable of expressing non-clustered GABAAR subtypes containing the Î ́ subunit. We have examined expression of chimeric subunits in which the large intracellular loops (IL) of Î32S and Î ́ subunits were exchanged. We show that while the Î32 IL is both necessary and central to the clustering process, it is not sufficient for clustering when incorporated into the Î ́ subunit. Thus, there are additional requirements other than the Î32-IL for receptor clustering that are as yet unidentified.

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAA and GABAB receptors. Recently, a novel form of GABAA receptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAA receptors underlie classical “phasic” GABAA receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAA receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAA receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This book highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAA receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAA receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.

Jasper's Basic Mechanisms, Fourth Edition, is the newest most ambitious and now clinically relevant publishing project to build on the four-decade legacy of the Jasper's series. In keeping with the original goal of searching for "a better understanding of the epilepsies and rational methods of prevention and treatment.", the book represents an encyclopedic compendium neurobiological mechanisms of seizures, epileptogenesis, epilepsy genetics and comordid conditions. Of practical importance to the clinician, and new to this edition are disease mechanisms of genetic epilepsies and therapeutic approaches, ranging from novel antiepileptic drug targets to cell and gene therapies.

The NMDA receptor plays a critical role in the development of the central nervous system and in adult neuroplasticity, learning, and memory. Therefore, it is not surprising that this receptor has been widely studied. However, despite the importance of rhythms for the sustenance of life, this aspect of NMDAR function remains poorly studied. Written