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Title: Inhibiting inhibition : interactions amongst interneurons of the hippocampus
Author: Booker, Samuel A.
ISNI:       0000 0004 2710 9022
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2011
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Cortical networks comprise excitatory principal cells and interneurons (IN); the latter showing large neurochemical, morphological and physiological heterogeneity. GABA release from IN axon terminals activates fast ionotropic GABAA or slow metabotropic GABAB receptors (GABABR); ionotropic GABA mechanisms are well described in INs, whereas GABABR activity is less well understood. The primary aim of this thesis is to ascertain GABABR mediated inhibition in different IN types containing the neurochemicals parvalbumin (PV), cholecystokinin (CCK) or somatostatin (SSt). Using immunocytochemical techniques, at light and electron microscopic levels, we examined the cellular and subcellular expression of GABAB1 receptor subunits in these INs. Application of whole-cell patch clamp techniques in acute slices, allowed analysis of GABABR effects pre- and postsynaptically; in response to endogenous GABA release or pharmacological activation. Light microscopy showed GABAB1 expression in INs containing CCK or SSt, equivalent to CA1 pyramidal cells; with low expression in PV INs. Using electron microscopy, we detected GABAB1 receptor subunits in dendrites of CCK and PV INs, with densities equivalent or higher than CA1 pyramidal cell dendrites. Unexpectedly, SSt containing dendrites showed a lower density of GABAB1 receptor subunits. In axon terminals of CCK and PV containing INs, we found comparable densities of GABAB1 receptor subunits. Electrophysiological recordings confirmed the presence of functional postsynaptic GABABR in PV and CCK INs. GABABR-mediated slow inhibitory postsynaptic currents (IPSCs) had typically large amplitudes, but with high cell-to-cell variability in both IN types. Morphological separation of PV or CCK INs revealed slow IPSC amplitudes which were large in perisomatic inhibitory (PI)cells (30.8 ± 8.6 pA and 39.2 ± 5.5 pA, respectively) and small in dendritic inhibitory (DI) cells (4.0 ± 1.7 pA and 11.6 ± 2.4 pA, respectively). Consistently, SSt-immunoreactive DI INs exhibited very small IPSCs (1.5 ± 0.2 pA). Pharmacological activation of GABAB R by the selective agonist baclofen revealed variable amplitude whole-cell currents, confirming differences between IN subtypes. Examining presynaptic GABABR activity; we minimally stimulated str. pyramidale evoking monosynaptic IPSCs in CA1 pyramidal cells. IPSCs mediated by CCK or PV PI axons were pharmacologically isolated by CB1 or M2 receptor activation. Both monosynaptic responses were reduced by baclofen, albeit differentially so. To further investigate this effect we performed paired-recordings from PV or CCK INs coupled synaptically to CA1 pyramidal cells. Baclofen inhibited PV and CCK basket cell mediated IPSCs by 51% and 98%, respectively; with a smaller effect in DI INs. In summary, we have shown that functional GABABRs are expressed pre- and postsynaptically in hippocampal GABAergic INs; with distinct populations of INs under differential GABABR control. Postsynaptic inhibition was strong in PI INs, but weak or absent in DI INs, a relationship conserved presynaptically. The observed differential expression of GABABRs is likely to play a fundamental role in regulating the excitability and activity of GABAergic INs, regulating synaptic output and potentially contributing to network and oscillatory activity. Consequentially, during periods of high GABA release, GABABR activation could act as a switch, allowing DI INs to play a greater role in network inhibition, due to GABABR mediated inhibition of perisomatic-targeting INs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology