Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area

The activation of metabotropic glutamate receptors (mGluRs) leads to long-term depression (mGluR-LTD) at many synapses of the brain. The induction of mGluR-LTD is well characterized, whereas the mechanisms underlying its expression remain largely elusive. mGluR-LTD in the ventral tegmental area (VTA) efficiently reverses cocaine-induced strengthening of excitatory inputs onto dopamine neurons. We show that mGluR-LTD is expressed by an exchange of GluR2-lacking AMPA receptors for GluR2-containing receptors with a lower single-channel conductance. The synaptic insertion of GluR2 depends on de novo protein synthesis via rapid messenger RNA translation of GluR2. Regulated synthesis of GluR2 in the VTA is therefore required to reverse cocaine-induced synaptic plasticity.     

Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function

The physiological role of striatal cholinergic interneurons was investigated with immunotoxin-mediated cell targeting (IMCT). Unilateral cholinergic cell ablation caused an acute abnormal turning behavior. These mice showed gradual recovery but displayed abnormal turning by both excess stimulation and inhibition of dopamine actions. In the acute phase, basal ganglia function was shifted to a hyperactive state by stimulation and suppression of striatonigral and striatopallidal neurons, respectively. D1 and D2 dopamine receptors were then down-regulated, relieving dopamine-predominant synaptic perturbation but leaving a defect in controlling dopamine responses. The acetylcholine-dopamine interaction is concertedly and adaptively regulated for basal ganglia synaptic integration.     

Neuronal cytomechanics: the actin-based motility of growth cones

The patterns of synaptic connection that underlie brain function depend on the elaborate forms characteristic of neurons. It is therefore a central goal of neuroscience to understand the molecular basis for neuronal shape. Neuronal pathfinding during development is one major determinant of neuronal shape: growing nerve axons and dendrites must navigate, branch, and locate targets in response to extracellular cue molecules within the embryo. The leading tips of growing nerve processes, structures known as growth cones, contain especially high concentrations of the ubiquitous mechanochemical protein actin. Force generation involving this cytoskeletal molecule appears to be essential to the ability of growing nerve fibers to respond structurally to extracellular cues. New results from electronically enhanced light microscopy of living growth cones are helping to show how actin-based forces guide neurite growth and synapse formation.     

Dichotomous dopaminergic control of striatal synaptic plasticity

At synapses between cortical pyramidal neurons and principal striatal medium spiny neurons (MSNs), postsynaptic D1 and D2 dopamine (DA) receptors are postulated to be necessary for the induction of long-term potentiation and depression, respectively-forms of plasticity thought to underlie associative learning. Because these receptors are restricted to two distinct MSN populations, this postulate demands that synaptic plasticity be unidirectional in each cell type. Using brain slices from DA receptor transgenic mice, we show that this is not the case. Rather, DA plays complementary roles in these two types of MSN to ensure that synaptic plasticity is bidirectional and Hebbian. In models of Parkinson's disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms.     

Adenosine 3',5'-monophosphate: electrophysiological evidence for a role in synaptic transmission

Synaptic potentials and changes in resting membrane potentials of superior cervical ganglia of the rabbit were measured in the presence of adenosine 3',5'-monophosphate and agents that affect its metabolism. Adenosine 3',5'-monophosphate and its mono- and dibutyryl derivatives caused a hyperpolarization of the postganglionic neurons. Theophylline potentiated the slow inhibitory postsynaptic potential that follows synaptic transmission, as well as the hyperpolarization of postganglionic neurons caused by exogenous dopamine. Conversely, prostaglandin E(1) inhibited both the slow inhibitory postsynaptic potential and the dopamine-induced hyperpolarization. We hypothesize that the slow inhibitory postsynaptic potential as well as the dopamine-induced hyperpolarization result from increased amounts of adenosine 3'5'-monophosphate in the postganglionic neurons. The dibutyryl derivative of guanosine 3'5'-monophosphate caused a depolarization of the postganglionic neurons, which is consistent with the possibility that guanosine 3'5'-monophosphate mediates synaptic transmission at muscarinic cholinergic synapses.     

Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex

Dominance hierarchy has a profound impact on animals' survival, health, and reproductive success, but its neural circuit mechanism is virtually unknown. We found that dominance ranking in mice is transitive, relatively stable, and highly correlates among multiple behavior measures. Recording from layer V pyramidal neurons of the medial prefrontal cortex (mPFC) showed higher strength of excitatory synaptic inputs in mice with higher ranking, as compared with their subordinate cage mates. Furthermore, molecular manipulations that resulted in an increase and decrease in the synaptic efficacy in dorsal mPFC neurons caused an upward and downward movement in the social rank, respectively. These results provide direct evidence for mPFC's involvement in social hierarchy and suggest that social rank is plastic and can be tuned by altering synaptic strength in mPFC pyramidal cells.     

Signal-processing machines at the postsynaptic density

Dendrites of individual neurons in the vertebrate central nervous system are contacted by thousands of synaptic terminals relaying information about the environment. The postsynaptic membrane at each synaptic terminal is the first place where information is processed as it converges on the dendrite. At the postsynaptic membrane of excitatory synapses, neurotransmitter receptors are attached to large protein "signaling machines" that delicately regulate the strength of synaptic transmission. These machines are visible in the electron microscope and are called the postsynaptic density. By changing synaptic strength in response to neural activity, the postsynaptic density contributes to information processing and the formation of memories.     

Diversity and dynamics of dendritic signaling

Communication between neurons in the brain occurs primarily through synapses made onto elaborate treelike structures called dendrites. New electrical and optical recording techniques have led to tremendous advances in our understanding of how dendrites contribute to neuronal computation in the mammalian brain. The varied morphology and electrical and chemical properties of dendrites enable a spectrum of local and long-range signaling, defining the input-output relationship of neurons and the rules for induction of synaptic plasticity. In this way, diversity in dendritic signaling allows individual neurons to carry out specialized functions within their respective networks.     

Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity

Activity shapes the structure of neurons and their circuits. Two-photon imaging of CA1 neurons expressing enhanced green fluorescent protein in developing hippocampal slices from rat brains was used to characterize dendritic morphogenesis in response to synaptic activity. High-frequency focal synaptic stimulation induced a period (longer than 30 minutes) of enhanced growth of small filopodia-like protrusions (typically less than 5 micrometers long). Synaptically evoked growth was long-lasting and localized to dendritic regions close (less than 50 micrometers) to the stimulating electrode and was prevented by blockade of N-methyl-D-aspartate receptors. Thus, synaptic activation can produce rapid input-specific changes in dendritic structure. Such persistent structural changes could contribute to the development of neural circuitry.     

Effect of adenosine 3',5'-monophosphate on neuronal pacemaker activity: a voltage clamp analysis

Bursting pacemaker activity in nerve cells can be modified for long periods by synaptic input of short duration. There is evidence that cyclic nucleotides may play a role in these modifications. The predominant effect of elevated levels of adenosine 3',5'-monophosphate in Aplysia neurons was an increased slope conductance to hyperpolarizing pulses, evident in voltage clamp records. A similar increase in slope conductance was seen as one component of maximum strength synaptic stimulation, which is consistent with the idea that cyclic nucleotides are important in the expression of synaptic alteration of bursting pacemaker activity.     

Simulation of paleocortex performs hierarchical clustering

Simulations were performed of layers I and II of olfactory paleocortex, as connected to its primary input structure, olfactory bulb. Induction of synaptic long-term potentiation by means of repetitive sampling of inputs caused the simulation to organize encodings of learned cues into a hierarchical memory that uncovered statistical relationships in the cue environment, corresponding to the performance of hierarchical clustering by the biological network. Simplification led to characterization of those parts of the network responsible for the mechanism, resulting in a novel, efficient algorithm for hierarchical clustering. The hypothesis is put forward that these corticobulbar networks and circuitry of similar design in other brain regions contain computational elements sufficient to construct perceptual hierarchies for use in recognizing environmental cues.     

Emergence of posttetanic potentiation as a distinct phase in the differentiation of an identified synapse in Aplysia

The developmental time course of posttetanic potentiation was studied at an identified chemical synapse. In stage 11 juveniles (3 weeks after metamorphosis), the synaptic connections made by cholinergic neuron L10 onto postsynaptic neurons L2 to L6 were present but showed no posttetanic potentiation. In stage 13 adults (12 weeks after metamorphosis), the same tetanus resulted in an increase of 300 percent in the synaptic potential. A similar pattern was observed at two other identified synapses in the abdominal ganglion. Thus, the initial steps in synapse formation do not include the expression of this plastic capability. Rather, at least 10 weeks is required between the onset of synaptic function and the final expression of mature synaptic properties.     

PSD-95 involvement in maturation of excitatory synapses

PSD-95 is a neuronal PDZ protein that associates with receptors and cytoskeletal elements at synapses, but whose function is uncertain. We found that overexpression of PSD-95 in hippocampal neurons can drive maturation of glutamatergic synapses. PSD-95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD-95 but did not rely on its guanylate kinase domain. PSD-95 expression also increased the number and size of dendritic spines. These results demonstrate that PSD-95 can orchestrate synaptic development and are suggestive of roles for PSD-95 in synapse stabilization and plasticity.     

Target-dependent structural changes accompanying long-term synaptic facilitation in Aplysia neurons

The mechanisms underlying structural changes that accompany learning and memory have been difficult to investigate in the intact nervous system. In order to make these changes more accessible for experimental analysis, dissociated cell culture and low-light-level video microscopy were used to examine Aplysia sensory neurons in the presence or absence of their target cells. Repeated applications of serotonin, a facilitating transmitter important in behavioral dishabituation and sensitization, produced growth of the sensory neurons that paralleled the long-term enhancement of synaptic strength. This growth required the presence of the postsynaptic motor neuron. Thus, both the structural changes and the synaptic facilitation of Aplysia sensorimotor synapses accompanying long-term behavioral sensitization can be produced in vitro by applying a single facilitating transmitter repeatedly. These structural changes depend on an interaction of the presynaptic neuron with an appropriate postsynaptic target.     

Rapid rewiring of arcuate nucleus feeding circuits by leptin

The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects.     

Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli

Dopamine neurons play a key role in reward-related behaviors. Reward coding theories predict that dopamine neurons will be inhibited by or will not respond to aversive stimuli. Paradoxically, between 3 and 49% of presumed dopamine neurons are excited by aversive stimuli. We found that, in the ventral tegmental area of anesthetized rats, the population of presumed dopamine neurons that are excited by aversive stimuli is actually not dopaminergic. The identified dopamine neurons were inhibited by the aversive stimulus. These findings suggest that dopamine neurons are specifically excited by reward and that a population of nondopamine neurons is excited by aversive stimuli.     

Regulation of dendritic protein synthesis by miniature synaptic events

We examined dendritic protein synthesis after a prolonged blockade of action potentials alone and after a blockade of both action potentials and miniature excitatory synaptic events (minis). Relative to controls, dendrites exposed to a prolonged blockade of action potentials showed diminished protein synthesis. Dendrites in which both action potentials and minis were blocked showed enhanced protein synthesis, suggesting that minis inhibit dendritic translation. When minis were acutely blocked or stimulated, an immediate increase or decrease, respectively, in dendritic translation was observed. Taken together, these results reveal a role for miniature synaptic events in the acute regulation of dendritic protein synthesis in neurons.     

Intrahippocampal septal grafts ameliorate learning impairments in aged rats

Grafts of fetal septal tissue rich in cholinergic neurons were implanted as a dissociated cell suspension into the depth of the hippocampal formation in aged rats with severe impairments in spatial learning abilities. After 2 1/2 to 3 months, the rats with grafts, but not the controls, had improved their performance in a spatial learning test. Their improvement was due, at least in part, to an increased ability to use spatial cues in the task. In all animals the grafts had produced an extensive acetylcholinesterase-positive terminal network in the surrounding host hippocampal formation. Thus, the action of cholinergic neurons in the graft onto elements in the host hippocampal circuitry may be a necessary, but perhaps not sufficient, prerequisite for the observed functional recovery.     

Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons

Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.     

Strychnine- and pentylenetetrazol-induced changes of excitability in aplysia neurons

In Aplysia neurons isolated from their synaptic input strychnine induces doublet discharges associated in voltage clamp with a decrease in the threshold for the inward current and a reduction and delayed onset of the outward current. Pentylenetetrazol causes oscillations and bursting behavior in normally silent cells together with an increased inactivation of the delayed outward current and induced or enhanced anomalous rectification.