Summary Throughout the brain postsynaptic neurons release substances from their cell bodies and dendrites that regulate the strength of the synapses they receive. Diverse chemical messengers have been implicated in retrograde signaling from postsynaptic neurons to presynaptic boutons. Here we provide an overview of the signaling systems that lead to rapid changes in synaptic strength. We consider the capabilities, specializations and physiological roles of each type of signaling system.

Summary Inhibitory projection neurons in the deep cerebellar nuclei (DCN) provide GABAergic input to neurons of the inferior olive (IO) that in turn produce climbing fiber synapses onto Purkinje cells. Anatomical evidence suggests that DCN to IO synapses control electrical coupling between IO neurons. In vivo studies suggest that they also control the synchrony of IO neurons and play an important role in cerebellar learning. Here we provide the first electrophysiological description of the DCN to IO synapse. Remarkably, GABA release was almost exclusively asynchronous, with little conventional synchronous release. Synaptic transmission was extremely frequency dependent, with low-frequency stimulation being largely ineffective. However, due to the prominence of asynchronous release, stimulation at frequencies above 10 Hz evoked steady-state inhibitory currents. These properties seem ideally suited to transform the firing rate of DCN neurons into sustained inhibition that both suppresses the firing of IO cells and regulates the effective coupling between IO neurons.

Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this nonassociative neural plasticity using in vivo and in vitro preparations and to determine its role in cortical odor adaptation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants. The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10 -20 sec of the post-train recovery period and a longer lasting (ϳ120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-␣-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the ␤-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the ␤ (15-35 Hz) spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo.

Odor perception is situational, contextual, and ecological. Odors are not stored in memory as unique entities. Rather, they are always interrelated with other sensory perceptions . . . that happen to coincide with them.-Engen (1991, p 86-87) The field of olfaction has experienced explosive growth over the past decade toward understanding the molecular events underlying transduction, mechanisms of spatiotemporal central processing, and neural correlates of olfactory perception and cognition. A thread running through each of these broad components that define olfaction appears to be their dynamic nature. How odors are processed, at both the behavioral and neural level, is heavily dependent on past experience, current environmental context, and internal state. The neural plasticity that allows this dynamic processing is expressed nearly ubiquitously in the olfactory pathway, from olfactory receptor neurons to the higher-order cortex, and includes mechanisms ranging from changes in membrane excitability to changes in synaptic efficacy to neurogenesis and apoptosis.The olfactory system has proven to be an excellent model system for the study of the neurobiology of memory for several reasons. First, the olfactory system is phylogenetically highly conserved, and memory plays a critical role in many ecologically significant odorguided behaviors. Thus, many different animal models, ranging from Drosophila to primates, can be taken advantage of to address specific experimental questions. Second, the olfactory pathway is relatively short and perhaps simplified compared to mammalian thalamocortical systems, with second-order neurons projecting directly to a well-described trilaminar sensory cortex. Third, the olfactory system has very strong anatomical ties to the limbic system; for example, both the lateral nucleus of the amygdala and the hippocampal dentate gyrus are three synapses from olfactory receptor neurons in the nose. Finally, the olfactory system is heavily innervated by well-defined neuromodulatory systems known to be important for memory and neural plasticity.This review will describe recent findings regarding plasticity in the mammalian olfactory system that we believe have general relevance for understanding the neurobiology of memory. Following a brief overview of olfactory system functional anatomy, we will review types of neural plasticity expressed in the olfactory system and then how these mechanisms relate to the diverse components of behavioral olfactory memory. Finally, we will attempt to identify some emergent principles of the neurobiology of olfactory memory and outline some potential future directions. Olfactory System OrganizationVery simply put, the primary olfactory pathway includes the olfactory receptor neurons in the nose (or antenna in many invertebrates), second-order neurons and affiliated We are rapidly advancing toward an understanding of the molecular events underlying odor transduction, mechanisms of spatiotemporal central odor processing, and neural correlates of olfactory percept...

5-HT 2 -type serotonin receptors (5-HT 2 Rs) are widely expressed throughout the brain and mediate many of the modulatory effects of serotonin. It has been thought that postsynaptic 5-HT 2 Rs act primarily by depolarizing neurons and thereby increasing their excitability. However, it is also known that 5-HT 2 Rs are coupled to G q/11 -type G-proteins and that some other types of G q/11 -coupled receptors can regulate synapses by evoking endocannabinoid release and activating presynaptic cannabinoid-type 1 receptors (CB 1 Rs). Here, we examine whether activation of 5-HT 2 Rs can regulate synapses through such a mechanism by studying excitatory synapses onto cells in the inferior olive (IO). These cells express 5-HT 2 Rs on their soma and dendrites, and the IO receives extensive serotonergic input. We find that the excitatory synaptic inputs onto IO cells are strongly suppressed by serotonin receptor agonists as well as release of endogenous serotonin. Both 5-HT 2 Rs and 5-HT 1B Rs contribute to this modulation by decreasing the probability of glutamate release from presynaptic boutons. The suppression by 5-HT 2 Rs is of particular interest because it is prevented by CB 1 R antagonists, and 5-HT 2 Rs are thought to be located only postsynaptically on IO cells. Our results indicate that serotonin activates 5-HT 2 Rs on IO neurons, thereby releasing endocannabinoids that act retrogradely to suppress glutamate release by activating presynaptic CB 1 Rs. These findings establish a link between serotonin signaling and endocannabinoid signaling. Based on the extensive distribution of 5-HT 2 Rs and CB 1 Rs, it seems likely that this mechanism could mediate many of the actions of 5-HT 2 Rs throughout the brain.