Sensory experience powerfully regulates the development of circuits in the cerebral cortex, contributing to late stages of cortical development. The cellular mechanisms by which experience alters cortical circuits are not yet understood. This process can be studied in sensory areas of cerebral cortex, which contain orderly sensory maps whose topography is altered by sensory experience. The standard model posits that rapid components of map plasticity reflect long-term synaptic potentiation (LTP) and depression (LTD), mediated by N-methyl-D-aspartate (NMDA)-type glutamate receptors, at specific cortical excitatory synapses. Recent evidence has supported this model by directly detecting LTP and LTD induced at cortical synapses by sensory experience. However, new findings suggest that during early critical periods, LTD at many cortical synapses does not operate by classical, NMDA-dependent mechanisms, but instead involves retrograde signaling via the newly discovered endocannabinoid system and cannabinoid (CB) receptors. The cellular signaling pathways for CB-dependent LTD in cortex are not understood. We propose to elucidate these mechanisms in the whisker region of rodent somatosensory cortex. We will also test whether, as these findings suggest, CB receptors play an unexpected causal role in development and plasticity of cortical circuits. These experiments will expand current models of experience-dependent cortical development beyond NMDA-dependent LTP and LTD, to include cannabinoid-dependent mechanisms. Results may suggest novel therapeutic strategies for plasticity-related neurological disorders, including mental retardation, autism, and learning disability. Involvement of cannabinoid signaling pathways in cortical development may also have major implications for cannabinoid abuse in children and during fetal development.
This research will identify the cellular and molecular mechanisms for late, activity-dependent stages of brain development, in which sensory experience refines and optimizes brain circuits. Understanding these mechanisms will enable development of novel therapeutic strategies for neurodevelopmental disorders including mental retardation and autism. Because one major focus is to understand the natural role of cannabinoid receptor proteins in brain development, results could also have important implications for cannabinoid abuse.
Showing the most recent 10 out of 15 publications
