Naomi Stow

The mammalian cerebral cortex encompasses many distinct brain regions, and functions of these regions are direct reflections on the number and distribution of many types of neurons throughout embryogenesis and early stages of postnatal development. Thalamocortical axons (TCAs) are the fundamental bridges between the thalamus and the cortex. It is known that during postnatal development, glutamatergic synapses between TCAs and layer 4 neurons influence functional and cytoarchitectural maturation of the sensory cortex. The N-methyl-D-aspartate (NMDA) receptor is one of the primary glutamate receptors, and can be found in large concentrations as early as late embryonic brains before synapses form, implying that the NMDA receptor could have an important early role in neurodevelopment, including the generation of distinct types of neocortical neurons. Additional impacts of glutamate signaling in early embryogenesis are demonstrated in human cases, specifically pertaining to mutations of GRIN1 (an obligatory NMDA receptor subunit) or GRIN2B which have been shown to have a positive correlation with intellectual disabilities, epilepsy, and autism spectrum disorders. Because early developmental roles of TCA-derived glutamate in neocortex is unknown, we first generated thalamus-specific vGluT2 (vesicular glutamate transporter 2) knockout mice, which are deficient in glutamate release from TCAs. We found that at the neonatal stage, there is a decrease in the numbers of both layer 4 and layer 2/3 neurons in the primary somatosensory cortex. Based on these results, I am currently analyzing cortex-specific Grin1 knockout mice in order to test if this early requirement of glutamate in cortical neurogenesis is mediated through NMDA receptors.