Title: Compartmentalization and modulation of synaptic signaling in dendrites and spines
Description: Spines of principal neurons form the structural basis that biochemically compartmentalizes synaptic signaling. Most interneurons lack spines suggesting that they are incapable of synapse-specific compartmentalization and plasticity. Spatial confinement of synaptic calcium (Ca) signals has been demonstrated in some interneurons but the mechanisms for such compartmentalization are unknown. In addition it is unknown if compartmentalization determines or correlates with the spatial extent of Ca-dependent processes and plasticity. We show that synapses between parallel fibers and stellate cells (SCs) from acute rat cerebellar slices undergo a novel form of long term depression that is limited to activated synapses and depends on increases in [Ca], and cannabinoid 1 receptor (CB1R) activation. To understand how synapse-specific plasticity is induced by diffusible messengers in aspiny dendrites, we examined diffusion of Ca and small molecules within SC dendrites. Ca diffusion is severely restricted due to interactions with parvalbumin and a general barrier to small molecule mobility. Thus SC dendrites spatially restrict signaling cascades that trigger the selective regulation of active synapses.

Intrinsic cholinergic transmission via the activation of muscarinic acetylcholine receptors (mAchRs) modulates excitatory synaptic transmission onto medium spiny neurons (MSNs), the principal projection neuron in the striatum. It is unclear if activation of mAchRs modulates postsynaptic glutamate receptors or whether the locus of modulation is purely presynaptic. Using 2-photon glutamate uncaging to activate AMPA- (AMPARs) or NMDA-type glutamate receptors (NMDARs) in single MSN spines from rat acute slices, we show that steady-state mAchR activation has no effect on either receptor subtype. Optical quantal analysis of NMDAR-mediated Ca signals reveals that activation of mAchRs decreases the presynaptic probability and postsynaptic potency of glutamate release suggesting that multivesicular release occurs at these synapses. An additional manipulation that decreases probability of release also reduced the potency of postsynaptic responses. Thus, mAchRs modulate the potency of postsynaptic responses by decreasing the number of vesicles released by excitatory terminals.