1. The hyperpolarization-activated current (Ih) and its role in pacemaking activity in rat hippocampal stratum oriens-alveus interneurones was studied using whole-cell and perforated patch-clamp configurations.2. Voltage-clamp recordings revealed Ih as a slowly activating, inward current, activated by hyperpolarizing steps (holding potential, Vh = -40 mV), with a reversal potential close to -30 mV. Its activation curve ranged from -50 to -120 mV with a mid-activation point of -84-1 mV.3. Ih was blocked by external application of Cs' (2-5 mM) and ZD7288 (100 /M), but not by Ba2+ (1 mM).4. Ih was potentiated by both noradrenaline and isoprenaline by a mechanism consistent with a shift in the Ih activation curve.5. Under current-clamp conditions (Vh = -60 mV), ZD7288 induced a membrane hyperpolarization concomitant with an increase in the membrane input resistance and abolished the voltage sag generated by hyperpolarizing current injection. 6. Analysis of the current-discharge relationship revealed that block of Ih differentially increased the firing frequency of spikes occurring early in the train compared with those occurring late in the discharge. 7. When applied to spontaneously firing cells, ZD7288 reduced the firing frequency by selectively altering the time course of the interspike interval, while minimally affecting other action potential characteristics. Similarly, isoprenaline increased the spontaneous firing frequency by an effect exclusively on the after-hyperpolarization and interspike interval. 8. These results provide evidence for the involvement of Ih in the excitability and generation of spontaneous firing in hippocampal stratum oriens-alveus interneurones.
Inhibitory postsynaptic currents (IPSCs) evoked in CA1 pyramidal cells (n= 46) by identified interneurones (n= 43) located in str. oriens were recorded in order to compare their functional properties and to determine the effect of synapse location on the apparent IPSC kinetics as recorded using somatic voltage clamp at ‐70 mV and nearly symmetrical [Cl−]. Five types of visualised presynaptic interneurone, oriens‐lacunosum moleculare (O‐LMC), basket (BC), axo‐axonic (AAC), bistratified (BiC) and oriens‐bistratified (O‐BiC) cells, were distinguished by immunocytochemistry and/or synapse location using light and electron microscopy. Somatostatin immunoreactive O‐LMCs, innervating the most distal dendritic shafts and spines, evoked the smallest amplitude (26 ± 10 pA, s.e.m., n= 8) and slowest IPSCs (10‐90 % rise time, 6.2 ± 0.6 ms; decay, 20.8 ± 1.7 ms, n= 8), with no paired‐pulse modulation of the second IPSC (93 ± 4 %) at 100 ms interspike interval. In contrast, parvalbumin‐positive AACs evoked larger amplitude (308 ± 103 pA, n= 7) and kinetically faster (rise time, 0.8 ± 0.1 ms; decay 11.2 ± 0.9 ms, n= 7) IPSCs showing paired‐pulse depression (to 68 ± 5 %, n= 6). Parvalbumin‐ or CCK‐positive BCs (n= 9) terminating on soma/dendrites, BiCs (n= 4) and O‐BiCs (n=7) innervating dendrites evoked IPSCs with intermediate kinetic parameters. The properties of IPSCs and sensitivity to bicuculline indicated that they were mediated by GABAA receptors. In three cases, kinetically complex, multiphasic IPSCs, evoked by an action potential in the recorded basket cells, suggested that coupled interneurones, possibly through electrotonic junctions, converged on the same postsynaptic neurone. The population of O‐BiCs (4 of 4 somatostatin positive) characterised in this study had horizontal dendrites restricted to str. oriens/alveus and innervated stratum radiatum and oriens. Other BiCs had radial dendrites as described earlier. The parameters of IPSCs evoked by BiCs and O‐BiCs showed the largest cell to cell variation, and a single interneurone could evoke both small and slow as well as large and relatively fast IPSCs. The kinetic properties of the somatically recorded postsynaptic current are correlated with the innervated cell surface domain. A significant correlation of rise and decay times for the overall population of unitary IPSCs suggests that electrotonic filtering of distal responses is a major factor for the location and cell type specific differences of unitary IPSCs, but molecular heterogeneity of postsynaptic GABAA receptors may also contribute to the observed kinetic differences. Furthermore, domain specific differences in the short‐term plasticity of the postsynaptic response indicate a differentiation of interneurones in activity‐dependent responses.
Mice completely deficient for Dvl1, one of three mouse homologs of the Drosophila segment polarity gene Dishevelled, were created by gene targeting. Dvl1-deficient mice are viable, fertile, and structurally normal. Surprisingly, these mice exhibited reduced social interaction, including differences in whisker trimming, deficits in nest-building, less huddling contact during home cage sleeping, and subordinate responses in a social dominance test. Sensorimotor gating was abnormal, as measured by deficits in prepulse inhibition of acoustic and tactile startle. Thus, Dvl1 mutants may provide a model for aspects of several human psychiatric disorders. These results are consistent with an interpretation that common genetic mechanisms underlie abnormal social behavior and sensorimotor gating deficits and implicate Dvl1 in processes underlying complex behaviors.
1. Voltage and current clamp recordings were performed on CA1 rat hippocampal pyramidal cells using the patch clamp technique on "in vitro" slice preparations. 2. Hyperpolarizations from a holding potential of -35 mV elicited activation of the hyperpolarization-activated current (Ih) starting at voltages near -50 mV. 3. Ih recorded in voltage clamp conditions was blocked by external caesium (5 mM). 4. Raising the external K concentration from 4.35 to 24.35 mM sensibly increased the slope of the current-voltage (I/V) curve. Decreasing the external Na concentration from 133.5 to 33.5 mM depressed Ih without grossly altering the I/V slope. 5. The Ih fully activated I/V relation measured in the range -140 to -45 mV was linear with an extrapolated reversal at -17.0 +/- -1.6 (SE) mV. The current activation curve comprised the range between about -50 and -140 mV with a half-maximal activation at about -98 mV. 6. Perfusion of unclamped neurons with Cs (2 mM) hyperpolarized their resting potential by 3.8 +/- 0.2 mV and decreased the membrane conductance, as expected if Ih were activated at rest. Firing caused by depolarizing current steps was prevented by Cs-induced hyperpolarization, and could be restored by returning the membrane voltage to resting level by constant current injection. 7. The Cd-insensitive (medium-duration) afterhyperpolarization (AHP) elicited by a train of action potentials at -60 mV had an amplitude of 3.9 +/- 0.3 mV and was nearly fully abolished by 2 mM Cs (82.7 +/- 7.4%). Cs removed the depolarizing part of the afterhyperpolarization as expected if Ih activation was responsible for this phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Mossy fiber synaptic transmission at hippocampal CA3 pyramidal cells and interneurons was compared in rat brain slices to determine whether mossy terminals are functionally equivalent. Tetanic stimulation of mossy fibers induced long-term potentiation in pyramidal neurons but was either without effect or it induced depression at synapses onto interneurons. Unlike transmission onto pyramidal neurons, transmission onto interneurons was not potentiated after adenosine 3',5'-monophosphate (cAMP) activation. Furthermore, metabotropic glutamate receptor depression of transmission onto interneurons did not involve cAMP-dependent pathways. Thus, synaptic terminals arising from a common afferent pathway do not function as a single compartment but are specialized, depending on their postsynaptic target.
Excitatory synaptic activity in horizontal stratum oriens-alveus interneurons (OAIs) is driven by the recurrent collaterals of CA1 pyramidal cells and is strongly influenced by protocols that elicit synaptic plasticity in these principal neurons. Induction of LTD in the Schaffer collateral-CA1 pyramidal neuron synapse causes a passive down-regulation of stratum radiatum-evoked excitatory synaptic responses onto OAIs. In addition, we show that the strength of the temporoammonic input to the CA1 pyramidal neuron distal dendrites is regulated by OAI activity. The passive propagation of LTD to OAIs consequently disinhibits the direct entorhinal cortex-CA1 input, resulting in an enhanced excitation of CA1 pyramidal neurons by a mechanism not requiring activation of the trisynaptic pathway.
We have investigated NMDA receptor-dependent long-term potentiation (LTP) in distinct subtypes of nonpyramidal neurons of the CA1 hippocampus using induction protocols that permitted the differentiation between a direct form of LTP and plasticity resulting simply from the "passive propagation" of LTP occurring on CA1 pyramidal neurons. Two types of stratum (st.) oriens/ alveus interneurons received passive propagation of synaptic potentiation via the recurrent collaterals of CA1 pyramidal cells, but neither subtype possessed direct plasticity. In st. radiatum, two distinct classes of cells were observed: st. radiatum interneurons that showed neither direct nor propagated forms of synaptic plasticity, and "giant cells" for which EPSPs were robustly potentiated after a pairing protocol. This potentiation is similar to the LTP described in pyramidal cells, and its induction requires NMDA receptor activation. Thus, a large heterogeneity of synaptic plasticity exists in morphologically distinct neurons and suggests that complex changes in the CA1 network properties will occur after the induction of LTP.Key words: hippocampus; interneurons; LTP; plasticity; GABAergic; CA1 Synaptic plasticity of the CA1 subfield of the rat hippocampus has been extensively studied and characterized in pyramidal cells (Bliss and Collingridge, 1993;Malenka and Nicoll, 1993;Lisman, 1994). Although many issues still are under debate (Kullmann and Siegelbaum, 1995), the mechanisms involved in the induction of long-term potentiation (LTP) and long-term depression (LTD) have been elucidated (Bliss and Collingridge, 1993;Malenka, 1994). Both forms of plasticity require the activation of postsynaptic NMDA receptors (NMDARs) and an elevation of intracellular calcium levels (Collingridge et al., 1983; Malenka et al., 1988, Dudek andBear, 1992;Mulkey and Malenka, 1992), which lead to phosphorylation or dephosphorylation processes (Malinow et al., 1988;Malenka et al., 1989;Mulkey at al, 1993;Lisman, 1994).At the level of the hippocampal network, the net flow of information in the CA1 region is strongly modulated by the action of the nonpyramidal neurons, the cell bodies of which are distributed throughout all layers of the hippocampus (Lacaille et al., 1987(Lacaille et al., , 1989 Lacaille and Schwartzkroin, 1988a,b;Buhl et al., 1994;Sik et al., 1994Sik et al., , 1995Cobb et al., 1995;Maccaferri and McBain, 1995) (for review, see Freund and Buzsaki, 1996). The vast majority (ϳ90%) of these cells have been shown to be glutamate decarboxylase (GAD)-positive inhibitory interneurons (Woodson et al., 1989), the axons of which target different domains of the pyramidal cell dendritic tree (Gulyás et al., 1993;Buhl et al., 1994;Sik et al., 1995). Therefore, the possibility of additional synaptic plasticity occurring in nonpyramidal cells would greatly increase both the power and the level of complexity of signal processing in the CA1 subfield. Indeed, several reports have shown that after tetanic stimulation, changes occur in (1) evoked nonpyramidal cell f...
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