A. Kimberley McAllister, Ph.D.

Cellular and molecular mechanisms of synapse formation and plasticity in cortical development and disease

Research in my laboratory focuses on understanding the cellular and molecular mechanisms of synapse formation, competition, and elimination in the developing visual cortex. The main approach we use is to study the formation, persistence, and elimination of individual synapses between dissociated, cultured visual cortical neurons using time-lapse imaging. This is accomplished by simultaneously imaging the dynamics of pre- and postsynaptic proteins as they are recruited to, stabilized at, or removed from visualized synaptic sites. To complement this cell culture approach, we also use biochemistry, histology, electron microscopy, and whole-cell patch-clamp recording to investigate the cellular and molecular mechanisms that underlie the formation, stabilization, and/or elimination of visual cortical synapses. Specific signals that guide synapse formation and plasticity are studied by manipulating them locally at forming and/or mature synapses.  We are also studying the molecular signals that mediate the synapse-specific effects of neuronal activity in strengthening or weakening synapses during activity-dependent competition.

Using these approaches, we have discovered that synaptic vesicle proteins (STVs) and NMDA receptors (NRTPs) are trafficked in mobile transport packets in axons and dendrites, respectively, prior to synapse formation. STVs cycle during their transport along axonal membranes and growth cone filopodia and NRTPs undergo a novel form of transport, cycling with the membrane during pauses of movement along microtubules in dendrites. Axodendritic contact leads to bidirectional signaling which causes rapid recruitment of STVs and NRTPs to nascent synapses. Although current models imply that contact initiates signaling cascades that alter the velocity or directionality of synaptic precursors, we recently discovered that synaptogenic molecules instead alter precursor pausing behavior to cause their accumulation at nascent synapses. Moreover, sites of STV pausing are predefined sites for the selective formation of en passant synapses. Finally, both STVs and NRTPs can be recruited to nascent synapses through a novel, direct physical association with transmembrane synaptogenic molecules such as TrkB and neuroligin, respectively. Current research on this topic is focused on elucidating the role of activity, actin, lipid rafts, and intracellular signalign cascades on the recruitment of pre- and postsynaptic proteins to nascent synapses.

In addition to studying the cellular and molecular mechanisms of synapse formation and plasticity, we are also interested in elucidating the role for immune molecules in early postnatal cortical development. To that end, we have discovered thet MHC class I molecules negatively regulate the initial establishment of cortical connections. We are now working to identify the role for cytokines and synaptic activity in regulating MHCI expression as well as determining the mechanisms that MHCI uses to negatively regulate cortical connectivity. Since these immune molecules are implicated in several neurodevelopmental disorders, including autism and schizophrenia, MHCI molecules could mediate the effects of the environment on cortical connectivity both during normal development and in neurodevelopmental disorders.

Barrow SL, Constable JR, Clark E, El-Sabeawy F, McAllister AK*, and Washbourne PW* (2009) Neuroligin 1: a cell adhesion molecule that recruits PSD-95 and NMDA receptors by distinct mechanisms during synaptogenesis. Neural DevelopmentMay 18; 4:17.

Needleman LA and McAllister (2008) Seeing the light: insulin receptors and the CNS. Neuron 58:653-655.

Jelks, KAB, Wylie RL, Floyd CL, McAllister AK, and Wise PM. Estradiol targets pre and postsynaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons via an estrogen receptor-mediated process. J. Neurosci. 27:6903-6913.

McAllister AK (2007) Molecular mechanisms of CNS synapse formation. Annual Reviews of Neuroscience 30:425-450.

Gomes R, Hampton C, and McAllister AK. (2006) TrkB and synaptic proteins are colocalized and transported together during development of cortical neurons. Journal of Neuroscience 26: 11487-500.

Sabo SL, Gomes RG, and McAllister AK. (2006) Selective formation of synapses at defined sites along the axon shaft. Journal of Neuroscience 26: 10813- 10825.

Glynn MS and McAllister AK. (2006) Quantification of protein colocalization in cultured immunostained neurons. Nature Protocols 1:1287-1296.

Gage FH and McAllister AK (2005) Neuronal and glial cell biology. Current Opinion in Neurobiology 15: 497-499.

Washbourne PW, Liu X-B, Jones EG, and McAllister AK (2004) Exo/endocytic cycling of NMDA receptors during trafficking in neurons before synapse formation. Journal of Neuroscience, 24:8253-8264.

Sabo SL and McAllister AK (2003) Mobility and cycling of synaptic protein-containing vesicles in axonal growth cone filopodia, Nature Neuroscience 6: 1264-1269.

McAllister AK (2003) Biolistic transfection of cultured organotypic brain slices. In Methods in Molecular Biology, vol. 245: Gene Delivery to Mammalian Cells: Vol. 1: Nonviral Gene transfer Techniques, ed. W.C. Heiser. Totowa, NJ: Humana Press Inc.

Washbourne P, Bennett JE, and McAllister AK (2002) Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nature Neuroscience 5: 751-759.

Washbourne P and McAllister AK (2002) Transfection methods for neurons. Current Opinion in Neurobiology, 12: 566-573.

McAllister AK (2000) Biolistic transfection of cortical neurons in both slice and dissociated cultures. Science: Sci STKE.2000 Sep 26;2000(51):PL1.

McAllister AK and Stevens CF (2000) Non-saturation of both AMPA and NMDA receptors at hippocampal synapses, Proc. Natl. Acad. Sci. USA 97: 6173-6178.

McAllister AK (2000) Cellular and molecular mechanisms of dendritic growth. Cerebral Cortex, 10: 963-973.

McAllister AK, Katz LC, and Lo DC (1999) The role of neurotrophins in synaptic plasticity. Annual Review of Neuroscience22: 295-318.

Department of Neurology

Neurobiology, Physiology and Behavior

Biochemistry and Molecular Biology

Neuroscience

Pharmacology and Toxicology