Neurodevelopment and developmental disabilities; learning, memory and synaptic plasticity; ion channels and synaptic function; neurotransmitter and neurotrophin receptors and cell signaling
Development of Adult-Generated Neurons
Most neurons in the brain are generated during embryogenesis. However, neural stem cells in discrete regions of the adult brain continuously produce newborn neurons that can functionally integrate by forming synapses with the existing neural circuitry. One of the regions where adult neurogenesis occurs is the dentate gyrus, an area that is involved learning and memory. My laboratory focuses on the mechanisms underlying functional maturation and synaptogenesis of newborn granule cells, the principal neurons in the dentate gyrus. We use a variety of techniques to explore how newborn neurons survive and integrate, and how these processes are modified by aging, exercise and disease.
Several methods can be used to identify newborn neurons from the much larger population of mature neurons. One tool we use is the POMC-EGFP transgenic mouse. Pro-opiomelanocortin (POMC) is normally expressed in the pituitary and hypothalamus, but cryptic sequences in the POMC promoter also drive the expression of EGFP in newborn granule cells of the dentate gyrus. Because neurogenesis continues through adulthood, EGFP-labeled newborn neurons can be visualized in both young (above, left) and adult (above, right) mice. We also use complementary methods such as retroviral labeling and immunohistochemistry to identify newborn granule cells at various developmental stages.
One of our interests is how adult-generated neurons become "wired" into the adult neural network. Newborn neurons in the dentate gyrus first receive GABAergic synaptic input. GABA is the primary inhibitory neurotransmitter in the adult brain, and during development it also has a trophic role in neuronal maturation. We study how new neurons interact with their local environment to form synapses, and how these processes are altered in the aging and diseased brain. To the right is an image of three granule cells filled with biocytin (red) surrounded by unfilled granule cells (blue). Two of the granule cells received synaptic input (lower traces) in response to action potentials (upper traces) generated in a nearby GABAergic interneuron (upper left red cell).
Dieni CV, Panichi R, Aimone JB, Kuo CT, Wadiche JI, Overstreet-Wadiche L (2016) Low excitatory innervation balances high intrinsic excitability of immature dentate neurons. Nature Communications, 7:11313.
Overstreet-Wadiche L and McBain C (2015) Neurogliaform Cells in Cortical Circuits. Nature Reviews Neuroscience. 16:458-68.
Chancey JH, Poulson DJ, Wadiche JI, Overstreet-Wadiche L (2014) Hilar mossy cells provide the first glutamatergic synapses to adult born dentate granule cells. Journal of Neuroscience, 34:2349-54.
Dieni CV, Nietz AK, Panichi R, Wadiche JI, Overstreet-Wadiche L (2013) Distinct determinants of sparse activation during granule cell maturation. Journal of Neuroscience, 33:19131-42.
Chancey JH, Adlaf EW, Sapp MC, Pugh PC, Wadiche JI, Overstreet-Wadiche LS (2013) GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons. Journal of Neuroscience, 33:6614-22.
Dieni CV, Chancey JH, Overstreet-Wadiche LS (2013) Dynamic functions of GABA signaling during granule cell maturation. Frontiers in Neural Circuits, 6:113.
Markwardt S, Dieni C, Wadiche JI, Overstreet-Wadiche L (2011) Ivy/Neurogliaform interneurons coordinate activity in the neurogenic niche. Nature Neuroscience, 4:1407-9.
Pugh P, Adlaf E, Zhao C-S, Markwardt M, Gavin C, Wadiche JI, Overstreet-Wadiche L (2011) Enhanced integration of newborn neurons after neonatal insults. Frontiers in Neurogenesis, 5:45.
Markwardt SJ, Wadiche JI, Overstreet-Wadiche LS (2009) Input specific GABAergic signaling to newborn neurons in adult dentate gyrus. Journal of Neuroscience, 29: 15063-15072.
Zhao C-S, Overstreet-Wadiche L (2008) Integration of adult generated neurons during epileptogenesis. Epilepsia, 49 s5:3-12.
Ph.D., Northwestern University Medical School