AbstractMossy fiber synapses have properties that are fundamentally different from CA1 synapses. Frequency dependent facilitation and expression of an NMDAR-independent form of LTP are examples of the unique physiology of MF synapses. Presynaptic KARs have been shown to trigger these striking features of MF synapses. However, which KAR subunits are mainly responsible for these features has been under intense debate. Previous pharmacological studies emphasised the role of GluK1 whereas genetic studies demonstrated a role for GluK2. Therefore, we investigated the role of GluK1 and GluK2 subunits on MF characteristics with a combination of genetic and pharmacological tools.
We observed that GluK1 antagonism did not block LFF, PTP and LTP in the MF in Wistar rats, regardless of DCG-IV sensitivity. Next, we generated global GluK1 KO animals and validated them using the GluK1 specific agonist ATPA. In KOs, the degree of HFF and MF-LTP were comparable to WT confirming that in these conditions GluK1 is not involved in triggering these forms of plasticity. However, ACET did reduce the amplitude of the 5th response during HFF in WT, but not in KO implying the GluK1 subunit does contribute to this phenomenon.
GluK2 antagonism of kynurenic acid-derivatives, UBP2002 and UBP2038, were tested on MF function in global GluK1 KO mice to preclude any confounding actions at GluK1. In the presence of UBP2002, we did not observe MF-LTP and the degree of PTP was comparable to WT. In addition, UBP2002 and UBP2038 significantly reduced the amplitude of the 5th response during HFF in a reversible manner and the degree of LFF after drug washing out was significantly increased. To clarify the role of presynaptic GluK1, DG-GluK1 KOs were generated, however, validation by ATPA was unsuccessful. Taken together, our results indicate that GluK1 plays a minor role whereas GluK2 contributes substantially to MF function.
|Date of Award||28 Nov 2019|
|Supervisor||Zuner A Bortolotto (Supervisor) & Graham Collingridge (Supervisor)|