Bennett, S; (2017) Neuromodulation of Spontaneous Network Activity in the Neonatal Hippocampus. Doctoral thesis , UCL (University College London).

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Abstract

Giant depolarising potentials (GDPs) are spontaneous network events generated by the depolarising action of GABA at early developmental stages (Ben-Ari et al., 1989). We set out to characterise their modulation by glutamatergic receptors and SK channels. GDPs measured from P5 CA1 pyramidal neurons were completely abolished by a GABAA receptor antagonist. Glutamate has been shown to be important for GDP initiation (Gaiarsa et al., 1990), and the addition of NMDA and AMPA increased the frequency of GDPs. The application of individual NMDAR and AMPAR antagonists did not affect GDPs; only when these two receptors were inhibited together was their frequency reduced. SK channel mRNA is present in the neonatal hippocampus (Gymnopoulos et al., 2014), but their functional role is unknown. An SK channel inhibitor depolarised the membrane potential and increased the duration of GDPs in P3 CA1 pyramidal neurons, an effect that was not mediated by NMDARs. SK channel enhancers had the opposite effect. Therefore SK channels are functionally expressed in the P3 hippocampus and able to affect physiologically relevant spontaneous network activity. mGluRs affect GDPs in CA3 neurons (Strata et al., 1995) and here we investigated the action of group 1 mGluRs (mGluR1 and mGluR5) on GDPs in the CA1 region. A group 1 mGluR agonist, DHPG, increased GDP frequency in P5 CA1 pyramidal neurons. When mGluR5 was inhibited, DHPG has a smaller effect, thereby suggesting mGluR5 is functionally expressed in the neonatal hippocampus and contributes to the regulation of GDPs. When mGluR1 in the CA1 region was antagonised, GDPs declined until they were abolished, demonstrating that this receptor is required to maintain a sustained GDP activity. Further experiments using mPSC recordings and NMDAR/AMPAR antagonists demonstrated that the modulatory effect on GDPs of mGluR1 was not mediated by either a change in neurotransmitter release or ionotropic glutamate receptors.

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