Department of
Psychological and Brain Sciences

Cellular and molecular mechanisms of brain development, cannabinoid signaling, cerebellum.

Placement and functional properties of synaptic contacts between neurons underlie all neural computations, from sensory perceptions to abstract thought and behavioral output. Mismatch in connectivity causes alterations in activity of neural circuits that are at the core of multiple neurological and psychiatric disorders. Although developmental steps leading to emergence of the mature cerebellar morphology, cytoarchitecture, and microcircuitry have been meticulously characterized, molecular mechanisms that orchestrate maturation of cerebellar circuits are much less understood. We strive to gain mechanistic understanding of the molecular signals regulating cellular behaviors that culminate in synaptic matchmaking and refinement, ultimately leading to the exquisite specificity of synaptic connectivity. Specifically, we focus on the role of cannabinoid signaling in directing development and function of cerebellar circuits, and in adjustment of cerebellum-modified behaviors. Questions under active investigation include:

• How do endogenous cannabinoids regulate cerebellar wiring?
• What are the molecular mechanisms of cell-type specific effects of cannabinoid signaling?
• Are exogenous cannabinoids teratogenic during cerebellar development?
• What are the structural, functional, and behavioral consequences of retrograde cannabinoid signaling in inhibitory cerebellar synapses?

We approach these questions experimentally in-vivo and in-vitro:

• Morphological, anatomical, histological and cytochemical analysis in conventional and conditional mouse mutants
• Axon tracing, analysis of neuron morphology, 3D reconstruction
• Immunohistochemistry, confocal microscopy
• Primary explant and dissociated neuronal cultures
• Mouse behavior

• Sgadò P., Genovesi S., Kalinovsky A., Zunino G., Macchi F., Allegra M., Murenu E., Provenzano G., Tripathi P. P., Casarosa S, Joyner AL, Bozzi Y. Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: Implications for autism spectrum disorders. Experimental Neurology. 2013 Jan 26.
• Wilson S. L., Kalinovsky A., Orvis G. D., Joyner A. L. Spatially Restricted and Developmentally Dynamic Expression of Engrailed Genes in Multiple Cerebellar Cell Types. Cerebellum. 2011 Sep;10(3):356-72.
• Kalinovsky A., Boukhtouche F., Blazeski R., Bornmann C., Suzuki N.,Development of Axon-Target Specificity of Ponto-Cerebellar Afferents. PLoS Biology. 2011 Feb 8;9(2):e1001013
• Kalinovsky A., Scheiffele P. Transcriptional Control of Synaptic Differentiation by Retrograde Signals. Current Opinions in Neurobiology. 2004, 14(3):272-9 (Review)