Developmental changes in kainate receptors in cortical network function and oscillogenesis

Abstract

Kainate receptors (KAR) mediate synaptic transmission at pre- and post- synaptic locations at excitatory and inhibitory synapses. KARs also have powerful roles in the synchronisation of neuronal networks at a physiological and pathological level. The medial entorhinal cortex (MEC) has been strongly linked to pathological synchrony, particularly in neurodevelopmental disorders such as epilepsy and schizophrenia. This thesis aims to determine the physiological functions of KARs in the MEC during development. My initial work focused on the developmental changes in the baseline background synaptic transmission in LII and LV MEC, followed by the developmental changes in the ability of KAR to modulate spontaneous transmitter release. I have provided evidence for the involvement of two types of KAR in excitatory glutamatergic neurotransmission in the juvenile rat MEC: 1) A tonically active GluK1-containing KAR located at presynaptic terminals, and 2) a postsynaptic non GluK1-containing KAR at recurrent excitatory synapses with roles in synchronised network activity. KAR modulation was largely the same in both age groups. For inhibitory neurotransmission, I have provided evidence for a presynaptic facilitatory GluK1-containing KAR at interneurone terminals, acting to tonically increase GABA release onto principal neurones, and a KAR which may be located on the soma/dendrites of interneurones, driving GABA release via direct excitation. However, in the immature MEC, activation of the GluK1-containing KAR caused a substantial increase in GABA release, which was not evident in juvenile rats, showing this receptor may be developmentally downregulated or have different levels of tonic activation. Next, I determined a developmental profile of oscillatory activity induced by KAR activation in the MEC. Synchronised activity was a slow beta frequency in the neonate MEC, compared to a gamma frequency in juvenile slices. Activity in LII showed a large age-dependent increase in amplitude which was not present in LV. Moreover, the increase in amplitude (LII) and frequency (LII & LV) coincided with the onset of eye-opening, and may bare consequences for the synaptic organisation of the MEC. Taken together, the results from this study show KARs have many roles in mediating synaptic transmission and synchronised neuronal activity in the MEC, and may have transient developmentally regulated roles in the immature MEC. This work has implications for understanding neuronal synchrony and normal development of cognitive function, and for neurodevelopmental disorders such as schizophrenia and epilepsy, which involve EC dysfunction.

Date of Award	5 Feb 2018
Original language	English
Awarding Institution	University of Bath
Supervisor	Roland Jones (Supervisor)