Sensory experience powerfully regulates development of brain circuits in the cerebral cortex, contributing to late stages of cortical development, and also to adult learning. The cellular mechanisms that enable experience to alter cortical circuits are not yet understood. These mechanisms can be studied in sensory areas of cerebral cortex, which contain orderly sensory maps whose topography is altered by recent patterns of sensory experience. The standard model for map plasticity posits that rapid components of 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. Supporting this model, recent studies have directly detected LTP and LTD induced at cortical synapses by sensory experience. However, new data suggest that LTD at many cortical synapses does not operate by classical, NMDA-dependent mechanisms, but instead involves retrograde signaling via the cannabinoid type 1 (CB1) receptors. The cellular signaling pathways for CB1-dependent LTD in cortex are not understood. We propose to elucidate these mechanisms, and to understand how CB1-LTD implements Hebbian coincidence detection for cortical plasticity. The whisker region of rodent somatosensory cortex is used as a model system. We will also test whether CB1 receptors play an unexpected causal role in development and plasticity of cortical circuits, as these findings suggest. In another advance, recent studies indicate that sensory experience regulates not only excitatory synapses, but also inhibitory circuits. The prevalence of inhibitory circuit plasticity, and its specific role in cortical circuit development and plasticity, is not known. We propose to identify specific inhibitory neurons and circuits that are regulated by sensory experience, and to characterize the cellular mechanisms for this plasticity. We will specifically explore the hypothesis that plasticity of inhibitory circuits acts homeostatically to maintain the balance between excitation and inhibition during map plasticity. Together, these experiments will expand current models of experience-dependent cortical development beyond NMDA-dependent LTP and LTD, to include cannabinoid-dependent mechanisms and inhibitory circuits. Results may suggest novel therapeutic strategies for plasticityrelated 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.
