Spontaneous electrical activity in the neonate is critical to synaptic refinement and epigenetic processes of neural development. Network bursts that contribute to circuit development are a hallmark of the young hippocampus when neurons are more excitable than in the mature CNS. Spontaneous activity of CA3 neurons in the hippocampus is largely dependent on intrinsic conductances that underlie the after hyperpolarization potential (AHP). This conductance can be dynamically regulated by a class of glutamate-gated receptors, kainate receptors (KARs), which have been prominently associated with neurodevelopmental and neuropsychiatric disorders. Neonatal KARs are potentially a key regulator of the AHP in the developing hippocampus~ however it is not known whether certain properties of neonatal KARs, (e.g. their editing status, their linkage to particular signaling pathways, or how they are activated), make them more likely to play this role in neonate versus the mature hippocampus. Here we propose to address these fundamental questions by determining how neonatal KARs produce long-lasting inhibition of AHPs to regulate excitability of hippocampal neurons. Overall these studies will define a role for neonatal KARs in regulating activity in the hippocampus and will address a gap in our knowledge about their specialized role in developing circuits.
In Aim 1 we will use in vitro electrophysiological recording to determine whether KARs play a role in regulating the spontaneous activity of CA3 hippocampal neurons. Recordings will be made from KAR knockout mice and mutant mice that express only the mature form of the receptor to determine how these manipulations affect spontaneous bursting of hippocampal neurons. KARs are predominantly extrasynaptic during early development raising the question of how they might be activated.
In Aim 2 we hypothesize that extrasynaptic KARs can be activated by ambient glutamate, and this form of tonic signaling is critical to their specialized function in the neonate. Finally, in Aim 3 we will determine how extrasynaptic hippocampal KARs might be activated in the neonate. We will test two specific hypotheses (i) that neonatal KARs are activated by synaptic glutamate (e.g. through spillover) or (ii) by glutamate released from a non-conventional mechanism (e.g. gliotransmission). Together these studies will determine the mechanism by which neonatal KARs regulate excitability in the developing hippocampus. Altered developmental processes in the neonate could ultimately contribute to some of the neurodevelopmental and neuropsychiatric disorders that are associated with KARs such as mental retardation, autism, schizophrenia, bipolar disorder, and epilepsy.
Activity dependent refinement of circuits and synapses is critical to proper development in the neonatal brain, and disruption of these processes can be the root of neurodevelopmental and neuropsychiatric disorders. Kainate receptors are glutamate-gated neurotransmitter receptors that are thought to play roles in regulating excitability of neurons. Here we will determine how neonatal kainate receptors might have long-lasting effects on cellular excitability, which might uniquely allow them to contribute o the development of hippocampal circuits.
| Xu, Jian; Marshall, John J; Fernandes, Herman B et al. (2017) Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice. Cell Rep 18:1848-1857 |
| Contractor, Anis (2013) Broadening roles for FMRP: big news for big potassium (BK) channels. Neuron 77:601-3 |
