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Numerous observations suggest diverse and modulatory roles for serotonin (5-HT) in cortex. Because of the diversity of cell types and multiple receptor subtypes and actions of 5-HT, it has proven difficult to determine the overall role of 5-HT in cortical function. To provide a broader perspective of cellular actions, we studied the effects of 5-HT on morphologically and physiologically identified pyramidal and nonpyramidal neurons from layers I-III of primary somatosensory and motor cortex. We found cell type-specific differences in response to 5-HT. Four cell types were observed in layer I: Cajal Retzius, pia surface, vertical axon, and horizontal axon cells. The physiology of these cells ranged from fast spiking (FS) to regular spiking (RS). In layers II-III, we observed interneurons with FS, RS, and late spiking physiology. Morphologically, these cells varied from bipolar to multipolar and included basket-like and chandelier cells. 5-HT depolarized or hyperpolarized pyramidal neurons and reduced the slow afterhyperpolarization and spike frequency. Consistent with a role in facilitating tonic inhibition, 5-HT2 receptor activation increased the frequency of spontaneous IPSCs in pyramidal neurons. In layers II-III, 70% of interneurons were depolarized by 5-HT. In layer I, 57% of cells with axonal projections to layers II-III (vertical axon) were depolarized by 5-HT, whereas 63% of cells whose axons remain in layer I (horizontal axon) were hyperpolarized by 5-HT. We propose a functional segregation of 5-HT effects on cortical information processing, based on the pattern of axonal arborization.

Transporters are thought to assist in the termination of synaptic transmission at some synapses by removing neurotransmitter from the synapse. To investigate the role of glutamate transport in shaping the time course of excitatory transmission at the mossy fiber-granule cell synapse, the effects of transport impairment were studied using whole-cell voltage- and current-clamp recordings in slices of rat cerebellum. Impairment of transport by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) produced a prolongation of the decay of the AMPA receptor-mediated current after a repetitive stimulus, as well as prolongation of single stimulus-evoked EPSCs when AMPA receptor desensitization was blocked. PDC also produced a prolongation of both single and repetitive-evoked NMDA receptor-mediated EPSCs. Enzymatic degradation of extracellular glutamate did not reverse the PDC-induced prolongation of AMPA receptor-mediated current after a repetitive stimulus, suggesting that transporter binding sites participate in limiting glutamate spillover. In current-clamp recordings, PDC dramatically increased the total area of the EPSP and the burst duration evoked by single and repetitive stimuli. These data indicate that glutamate transporters play a significant role in sculpting the time course of synaptic transmission at granule cell synapses, most likely by limiting the extent of glutamate spillover. The contribution of transporters is particularly striking during repetitive stimulus trains at physiologically relevant frequencies. Hence, the structural arrangement of the glomerulus may enhance the contribution of transporters to information processing by limiting the extent of glutamate spillover between adjacent synapses.

Previous studies indicate that a variety of pharmacological agents interfere with the prepulse inhibition of the acoustic startle (PPI) response including phencyclidine (PCP), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), amphetamine, and apomorphine. Strain differences have been observed in the ability of apomorphine to disrupt PPI, although the degree to which these strain differences occur after administration of nondopaminergic drugs or the degree to which differences can be observed in other models of dopamine (DA) receptor activation has not been elucidated. The present study tested the effects of apomorphine, amphetamine, 8-OH-DPAT, and PCP on PPI in the Sprague Dawley and Wistar rat strains. Because apomorphine disrupts PPI via activation of DA receptors in the nucleus accumbens, apomorphine-induced hyperlocomotion, also a behavioral model of nucleus accumbens DA receptor activation, was measured in both rat strains. Administration of PCP or 8-OH-DPAT attenuated PPI in both strains, whereas apomorphine and amphetamine only attenuated PPI in Wistar rats. The ability of apomorphine to increase motor activity in the absence of a startle-eliciting stimulus was similar in the two strains, as was apomorphine-induced hyperlocomotion. A time course analysis of the effects of apomorphine on startle response in Sprague Dawley rats found that changes in the magnitude of PPI followed changes in basic startle amplitude. Similarly, no apomorphine-induced attenuation of PPI was observed in Sprague Dawley rats after 6-OHDA-induced DA receptor supersensitivity in the nucleus accumbens. These data suggest a dissociation between the effects of DA receptor agonists in PPI and other behavioral models of DA receptor activation.

It is thought that galanin, a 29 amino acid neuropeptide, is involved in various neuronal functions, including the regulation of food intake and hormone release. Consistent with this idea, galanin receptors have been demonstrated throughout the brain, with high levels being observed in the hypothalamus. However, little is known about the mechanisms by which galanin elicits its actions in the brain. Therefore, we studied the effects of galanin and its analogs on synaptic transmission using an in vitro slice preparation of rat hypothalamus. In arcuate nucleus neurons, application of galanin resulted in an inhibition of evoked glutamatergic EPSCs and a decrease in paired-pulse depression, indicating a presynaptic action. The fragments galanin 1-16 and 1-15 produced a robust depression of synaptic transmission, whereas the fragment 3-29 produced a lesser degree of depression. The chimeric peptides C7, M15, M32, and M40, which have been reported to antagonize some actions of galanin, all produced varying degrees of depression of evoked EPSCs. In a minority of cases, C7, M15, and M40 antagonized the actions of galanin. Analysis of mEPSCs in the presence of TTX and Cd2+, or after application of alpha-latrotoxin, indicated a site of action for galanin downstream of Ca2+ entry. Thus, our data suggest that galanin acts via several subtypes of presynaptic receptors to depress synaptic transmission in the rat arcuate nucleus.

We examined the effects of peptides of the neuropeptide Y (NPY)/pancreatic polypeptide (PP) family on synaptic transmission in the arcuate nucleus in rat hypothalamic slices. Application of NPY produced two effects. In some cells NPY produced an outward current that had the properties of a K+ current. NPY also inhibited the evoked glutamatergic EPSC recorded in these arcuate neurons by a presynaptic mechanism. Although the effects of NPY on the K+ current reversed within a few minutes of washout of the peptide, its effects on the EPSC frequently were longer lasting (>30 min). Similar effects were observed using peptide YY or the NPY analog [Leu31, Pro34]NPY. Although K+ current activation by [Leu31,Pro34]NPY was blocked by the selective Y1 antagonist BIBP 3226, inhibition of the EPSC was blocked only partially. Other NPY-related peptides such as NPY(13-36), PP, and [D-Trp32]NPY also inhibited the EPSC. However, none of these peptides produced activation of the K+ current. Thus, activation of more than one NPY receptor produces synaptic inhibition in the arcuate nucleus. A Y1 receptor activates a K+ current postsynaptically, and several receptor types appear to inhibit the EPSC by a presynaptic mechanism.