The mechanistic underpinnings of the circuit-specific role of N-methyl-D-aspartate receptors (NMDARs) in disorders such as pediatric epilepsies are elusive, and so-far, there are limitations in regards to its treatment. This proposal aims to investigate the role of mutations involved in pediatric epilepsy in NMDARs expressed in the thalamo-cortical (TC) circuit, a known cause in seizures. The incidence of loss-of-function (LOF) NMDAR mutations in patients with neurological problems is high. NMDARs, involved in excitatory neurotransmission, are tetrameric complexes, comprised of GluN1 and GluN2 subunits (A-D), endowing the receptor with divergent properties. These subunits are expressed differentially in the TC circuit. The GluN2A NMDAR is of particular interest since it is a major locus for LOF mutations. Moreover, postnatal expression of GluN2A LOF NMDARs circumvents prenatal complications, enabling patients to survive with neurological problems that appear as GluN2A expression increases postnatally. Our preliminary data suggest that GluN2D expression and function overtakes that of GluN2A in the LOF mice model in an age-dependent manner. Additionally, we have shown that most anti-epileptic compounds work differently on GluN2A and GluN2D subunits. Single-channel data show unique channel properties for these subunits and their triheteromeric assemblies. This work identifies mechanisms underlying altered TC communications in a GluN2A LOF mouse model of epilepsy and ensuing changes in developmental NMDAR subunit expression profile in the thalamus. Altered synchronicity and hyperexcitability in the TC loop is correlated to pediatric epilepsy, encephalopathy, schizophrenia, channelopathies, autism spectrum disorder and other neurodegenerative conditions. Hence, this work will influence neuroscience research largely by building fundamental knowledge of critical brain circuits and receptor-level developmental milestones underlying neurodegenerative human conditions.