Hippocampal inhibitory interneurons play important roles in controlling the excitability and synchronization of pyramidal cells, but whether they express long-term synaptic plasticity that contributes to hippocampal network function remains uncertain. We found that pairing postsynaptic depolarization with -burst stimulation induced long-term potentiation (LTP) of putative singlefiber excitatory postsynaptic currents in interneurons. Either postsynaptic depolarization or -burst stimulation alone failed to induce LTP. LTP was expressed as a decrease in failure rates and an increase in excitatory postsynaptic current amplitude, independent of N-methyl-D-aspartate receptors, and dependent on metabotropic glutamate receptors subtype 1a. LTP was induced specifically in interneurons in stratum oriens and not in interneurons of stratum radiatum͞lacunosum-moleculare. Thus, excitatory synapses onto specific subtypes of inhibitory interneurons express a new form of hebbian LTP that will contribute to hippocampal network plasticity.L ong-term potentiation (LTP) is the enduring increase in strength of synaptic transmission observed after tetanization of afferents (1). This synaptic plasticity has been extensively studied at glutamate synapses onto CA1 pyramidal cells of the hippocampus, where multiple forms of LTP can be induced by activation of N-methyl-D-aspartate receptors (NMDARs) (1, 2), metabotropic glutamate receptors (mGluRs) (3), and voltagedependent Ca 2ϩ channels (4, 5).The hippocampal neuronal network is also composed of inhibitory interneurons, which control the excitability and synchronization of projection cells (6-8). Modeling studies suggest that plasticity at interneuron synapses is important for learning and recall by hippocampal neuronal networks (9). However, experimental evidence of long-term synaptic plasticity at input and͞or output synapses of hippocampal interneurons has been controversial (10-16). This uncertainty has been due, in part, to the heterogeneity of interneuron types present in the hippocampus and to the complexity of the network (6,17,18). An important confounding factor has been that LTP induced at pyramidal cell synapses by tetanic stimulation of Schaffer collaterals can passively propagate to interneurons through recurrent excitatory collaterals of pyramidal cells and can be confused with direct potentiation of excitatory inputs onto interneurons (19). In addition, the apparent absence in interneurons of Ca 2ϩ -calmodulin-dependent protein kinase II and calcineurin (20), two major components of the Ca 2ϩ -signaling cascades involved in the induction of NMDAR-dependent LTP and depression, has been argued to support the lack of synaptic plasticity in interneurons (19,20). Recently, however, long-term depression has been observed at excitatory synapses onto interneurons after trains of high-frequency stimulation, suggesting that synaptic plasticity can indeed occur directly in interneurons (13,15).In the present study, the issue of long-term synaptic plasticity at synapses directly on i...

Receptor tyrosine kinases (RTKs) are membrane spanning proteins with intrinsic kinase activity. Although these receptors are known to be involved in proliferation and differentiation of cells, their roles in regulating central synaptic transmission are largely unknown. In CA1 pyramidal neurons, activation of D2 class dopamine receptors depressed excitatory transmission mediated by the NMDA subtype of glutamate receptor. This depression resulted from the quinpirole-induced release of intracellular Ca(2+) and enhanced Ca(2+)-dependent inactivation of NMDA receptors. The dopamine receptor-mediated depression was dependent on the "transactivation" of PDGFRbeta. Therefore, RTK transactivation provides a novel mechanism of communication between dopaminergic and glutamatergic systems and might help to explain how reciprocal changes in these systems could be linked to the deficits in cognition, memory, and attention observed in schizophrenia and attention deficit hyperactivity disorder.

CA1 pyramidal cells become hyperexcitable following hippocampal kainate lesions. To examine if axonal sprouting contributes to this epileptiform activity, the local axonal arborization of CA1 pyramidal cells was examined after intracellular labelling with biocytin in hippocampal slices from control rats and in hyperexcitable slices obtained from rats treated with kainate (bilateral intracerebroventricular injections) 2-4 weeks previously. Biocytin-labelled cells with an axon that could be followed from the soma to the alveus were drawn and reconstructed with a camera lucida (15 cells from control slices and 14 cells from hyperexcitable slices). Local axonal arborizations were more extensive in cells of hyperexcitable slices. This increase in axon collaterals was generally seen in the alveus and in stratum oriens, but changes were more prominent in the latter. In stratum oriens, cells from hyperexcitable slices showed a significant increase in mean total axon length (1035 versus 373 mu m in control), in mean number of branching points (6.50 versus 0.67 in control) and in mean number of segment orders per axon (3.07 versus 1.47 in control). Their first-order axon segments were similar in length to those of control cells (236 versus 338 pm in control), but with significantly more branching points (2.86 versus 0.53 in control). Their second-order axon segments were significantly longer (381 versus 63 mu m in control) and also showed more branching points (2.71 versus 0.13 in control). Their third- and fourth-order axon segments were also longer and with more branching points. Under high-power light microscopic examination, biocytin-labelled axonal varicosities in cells of hyperexcitable slices were often seen in close apposition with their own dendrites, presumably making synaptic contact (five of nine cells examined). No such appositions were seen in any of the control cells (seven cells examined). These results indicate that, following kainate lesions, there is sprouting of local axon collaterals of CA1 pyramidal cells in stratum oriens and in the alveus. This local increase in axon collaterals may contribute to the epileptiform activity in the CA1 area by providing recurrent excitation via newly formed synaptic, and perhaps even autaptic, contacts with pyramidal cell dendrites.

TRPM2 is a Ca2+ -permeable member of the transient receptor potential melastatin family of cation channels whose activation by reactive oxygen/nitrogen species (ROS/RNS) and ADP-ribose (ADPR) is linked to cell death. While these channels are broadly expressed in the CNS, the presence of TRPM2 in neurons remains controversial and more specifically, ] i , activation of NMDA receptors (NMDARs), which are highly permeable to Ca 2+ , was also permissive for current development. Importantly, given the prominent vulnerability of CA1 neurons to free-radical-induced cell death, we confirmed that, with ADPR in the pipette, a brief application of NMDA could evoke a large inward current in CA1 pyramidal neurons from hippocampal slices that was abolished by the removal of extracellular Ca 2+ , consistent with TRPM2 activation. Such a current was absent in interneurons of CA1 stratum radiatum. Finally, infection of cultured hippocampal neurons with a TRPM2-specific short hairpin RNA (shRNA TRPM2 ) significantly reduced both the expression of TRPM2 and the amplitude of the ADPR-dependent current. Taken together, these results indicate that hippocampal pyramidal neurons possess functional TRPM2 channels whose activation by ADPR is functionally coupled to VDCCs and NMDARs through a rise in [Ca 2+ ] i

An experimental drug, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine, that facilitates glutamatergic transmission in brain after systemic administration was tested for its effects on the induction of long-term potentiation in the hippocampus of rats. Intraperitoneal injections of the drug markedly increased the degree and duration of long-term potentiation; similar results were obtained with an analogue of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine that was also found to improve retention of memory in a radial maze task and in an odor-matching problem. These results define tools for enhancing long-term potentiation in vivo and confirm an important prediction from the hypothesis that long-term potentiation is a substrate of memory.Long-term potentiation (LTP) is a stable increase in synaptic strength known to occur at a variety of sites in the forebrain after brief periods of high-frequency afferent stimulation (1-3). The characteristics of LTP, including rapid development (4), persistence (5, 6), and synapse specificity (7,8), are suggestive of a memory-encoding process; moreover, patterns of physiological activity that have a strong relationship with LTP induction (9-11) have been recorded from neurons during learning (12). The hypothesis, arising from these observations, that LTP is a substrate of memory predicts that manipulations that block the potentiation effect will cause anterograde amnesia and that manipulations that promote it will result in memory enhancement. While there have been a number of tests of the first prediction (13-16), the absence of drugs that facilitate LTP in vivo have precluded tests of the second.Previous work (17) has shown that 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine (BDP) increases the amplitude and duration of field excitatory postsynaptic potentials (EPSPs) recorded in vitro in slices of hippocampus while having little effect on the slope of responses. Studies with outside-out patches indicate that BDP modulates a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor-gated currents (18). After intraperitoneal (i.p.) injections and for 2-3 h, the drug influences monosynaptic responses in the dentate gyrus in vivo in a manner similar to that observed in slices (17). Since compounds that facilitate AMPA-receptormediated responses promote the induction of LTP in hippocampal slices (19), BDP is a candidate for an enhancer of the potentiation effect in vivo. The experiments described in the present paper indicate that i.p. injections of BDP or a related compound have a marked influence on LTP in freely moving rats and, as expected from the LTP-memory hypothesis, improve retention of spatial and olfactory information. MATERIALS AND METHODSTo assess the time course of biodistribution of BDP (Cortex Pharmaceuticals, Irvine, CA), the drug was radiolabeled with carbon-11 as described (20) and injected into rats under conditions that simulated the dosage and mode of administration to be used (see below) in testing its effects on LTP. Biodistribution and pharmacokinetics ...