Parasynaptic signalling by fast neurotransmitters: the cerebellar cortex.

Classic central synaptic transmission by fast neurotransmitters-glutamate, GABA or glycine-involves liberation from vesicles directly opposite postsynaptic receptors at junctions containing both a presynaptic active zone and a postsynaptic specialisation. Such classic transmission is thought to underlie much of the information transfer and processing in the brain. However, there also exist a substantial number of reports of signalling by the same transmitters outside this classic framework, whereby liberation and/or receptor activation occur beyond synaptic boundaries. We term these processes collectively parasynaptic signalling. Here, we describe the various forms of parasynaptic signalling and the available methods for distinguishing them from synaptic transmission. We then review the numerous reports of parasynaptic signalling in the cerebellar cortex, a structure whose specialised anatomy and synapses have facilitated studies of these mechanisms. We examine more generally the question of how the multiple signalling pathways might avoid interaction and address the possible functions of parasynaptic transmission, which in the cerebellar cortex include the regulation of network activity, glial tropism and the control of synaptic plasticity.

Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus.

Evidence that protein synthesis inhibitors induce amnesia in a variety of species and learning paradigms indicates that the consolidation of newly acquired information into stable memories requires the synthesis of new proteins. Because extinction of a response also requires acquisition of new information, extinction, like original learning, would be expected to require protein synthesis. The present experiments examined the involvement of protein synthesis in the hippocampus in the extinction of a learned fear-based response known to involve the hippocampus. Rats were trained in a one-trial inhibitory avoidance task in which they received footshock after stepping from a small platform to a grid floor. They were then given daily retention tests without footshock. The inhibitory response (e.g., remaining on the platform) gradually extinguished with repeated testing over several days. Footshock administered in a different context, instead of a retention test, prevented the extinction. Infusions of the protein synthesis inhibitor anisomycin (80 microg) into the CA1 region of the hippocampus (bilaterally) 10 min before inhibitory avoidance training impaired retention on all subsequent tests. Anisomycin infused into the hippocampus immediately after the 1st retention test blocked extinction of the response. Infusions administered before the 1st retention test induced a temporary (i.e., 1 day) reduction in retention performance and blocked subsequent extinction. These findings are consistent with other evidence that anisomycin blocks both the consolidation of original learning and extinction.

Facilitation and inhibition of retrieval in two aversive tasks in rats by intrahippocampal infusion of agonists of specific glutamate metabotropic receptor subtypes.

RATIONALE: The generic antagonist of glutamate metabotropic receptors (mGlus), MCPG, blocks retrieval of inhibitory avoidance when infused into the CA1 area of rat hippocampus. It was considered important to study the effect of agonists of different types of mGlus on retrieval both of this task and of a related one, contextual fear. OBJECTIVES: To measure the effect of three mGlu agonists (3HPG, which is selective to mGlu1; LCCG, which binds to mGlu2 and mGlu3; and LAP-4, which binds to mGlu4 and mGlu6), infused bilaterally into CA1, on the retrieval of one-trial inhibitory avoidance and contextual fear in rats. METHODS: Rats bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory avoidance or in a contextual fear task and tested for retention 24 h later. The drugs 3HPG, LCCG and LAP-4 were infused into CA1 at different concentration levels 10 min before retention testing. In addition, we studied the effect of these drugs on locomotor and exploratory activity measured in an open field, and on pro- and anti-conflict behaviour in an elevated plus-maze. RESULTS: 3HPG hindered, and LCCG and LAP-4 enhanced, retrieval of the two tasks. In all cases the effects were dose-dependent. The drugs had no effects on open field or plus maze behaviour. CONCLUSIONS: Retrieval of one-trial inhibitory avoidance and of contextual fear is regulated by mGlus in the CA1area of the rat hippocampus. The results suggest that mGlu2s, mGlu3s, mGlu4s and mGlu6s are necessary for retrieval and that mGlu1s play an inhibitory role. The effects are not explainable by nonspecific influences on locomotor or exploratory activity or anxiety levels.

Novelty enhances retrieval: molecular mechanisms involved in rat hippocampus.

Rats exposed to a novel environment just prior to or 1-2 h, but not 4 or 6 h, before retention testing exhibited an enhanced retrieval of a one-trial inhibitory avoidance training. The bilateral intrahippocampal infusion of PD098059, an inhibitor of mitogen-activated protein kinase (MAPK), the specific upstream activator of p42 and p44 MAPKs, given 10 min before the exposure to the novel environment, blocked the enhancing effect of novelty on memory retrieval. In addition, prenovelty infusion of DL-2-amino-5-phosphonovalerate (APV), an antagonist of glutamate NMDA receptors, produced similar effects. The exposure to the novel environment is associated with an activation of p42 and p44 MAPKs and an increase in the phosphorylation state of the transcription factor cAMP response element binding protein (CREB). No changes were observed in cAMP-dependent protein kinase (PKA) activity or in alpha-CAMKII activation. Taken together, our results indicate that novelty activates hippocampal MAPKs, which are necessary, along with glutamate NMDA receptors, for the enhancing effect of novelty on retrieval.

Participation of hippocampal metabotropic glutamate receptors, protein kinase A and mitogen-activated protein kinases in memory retrieval.

The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. In contrast to memory formation, the information about the molecular mechanisms of memory retrieval is surprisingly scarce and fragmentary. Here we show that pretest inhibition of the specific upstream activator of mitogen-activated protein kinase kinase, or of protein kinase A in the hippocampus, blocked retrieval of long-term memory for an inhibitory avoidance task, a hippocampal-dependent learning task. An activator of protein kinase A enhanced retrieval. Mitogen-activated protein kinase activation increased in the hippocampus during retrieval, while protein kinase A activity remained unchanged. Pretest intrahippocampal blockade of metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, but not N-methyl-D-aspartate receptors or calcium/calmodulin dependent-protein kinase II, impaired retrieval. Thus, recall of inhibitory avoidance activates mitogen-activated protein kinase, which is necessary, along with metabotropic glutamate receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, and protein kinase A, for long-term memory expression. Our results indicate that memory formation and retrieval may share some molecular mechanisms in the hippocampus.

Experience-dependent decrease in synaptically localized Fra-1.

The Fos family of transcription factors has been repeatedly shown to participate in the long-term neural responses associated with a variety of physiological stimuli, including activity-dependent plastic processes. Quite recently, several transcription factors have been found in synaptic regions, localized in dendrites and presynaptic terminals. Here we show that the transcription factor Fos-related antigen-1 (Fra-1) was detected in synaptosomes (Syn) and synaptic plasma membrane (SPM) fractions from the rat cerebral cortex and hippocampus as a single band migrating with M(r) 42-43 kDa. The 55-kDa c-Fos protein was also detected in syn and SPM fractions. Conversely, the inducible 62-65-kDa c-Fos is present in nuclear fractions from metrazole-treated animals (positive control), but not in Syn or SPM fractions. Furthermore, no Fra-2, Fos B or c-Jun immunoreactivities were detected in these same synaptic regions. DNA-mobility shift assays showed the presence of specific AP-1 binding activity in synaptic protein extracts. Immunoelectronmicroscopic analysis of cortical and hippocampal tissues revealed that Fra-1 and Fos-like immunoreactivities are localized in association with presynaptic plasma membranes. One trial inhibitory avoidance training, a hippocampal-dependent task, is associated with a time-dependent decrease (-31%) in Fra-1, but not in 55-kDa c-Fos, levels in hippocampal SPM fractions. In hippocampal homogenates, we do not detect significant changes in Fra-1 immunoreactivity, suggesting that this behavioural experience is probably accompanied by a subcellular redistribution of Fra-1 protein. These results suggest that Fra-1 may participate in the communication between synapse and the nucleus and in experience-dependent hippocampal plasticity.