Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus.

Activation of inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) can lead to the release of Ca(2+) from intracellular stores and propagating Ca(2+) waves. Previous studies of these proteins in neurons have focused on their distribution in adult tissue, whereas, recent functional studies have examined neural tissue extracted from prenatal and young postnatal animals. In this study we examined the distribution of InsP(3)R isotypes 1-3 and RyR isotypes 1-3 in rat hippocampus during postnatal maturation, with a focus on InsP(3)R1 because it is most prominent in the hippocampus. InsP(3)R1 was observed in pyramidal cells and granule cells, InsP(3)R2 immunoreactivity was observed in perivascular astrocytes and endothelial cells, and InsP(3)R3 immunoreactivity was detected in axon terminals located in stratum pyramidale of CA1 and microvessels in stratum radiatum. RyR1 immunolabeling was enriched in CA1, RyR2 was most intense in CA3 and the dentate gyrus, and RyR3 immunolabeling was detected in all subfields of the hippocampus, but was most intense in stratum lacunosum-moleculare. During maturation from 2 to 10 weeks of age there was a shift in InsP(3)R1 immunoreactivity from a high density in the proximal apical dendrites to a uniform distribution along the dendrites. Independent of age, InsP(3)R1 immunoreactivity was observed to form clusters within the primary apical dendrite and at dendritic bifurcations of pyramidal neurons. As CA1 pyramidal neurons matured, InsP(3)R1 was often co-localized with the Ca(2+) binding protein calbindin D-28k. In contrast, InsP(3)R1 immunolabel was never co-localized with calbindin D-28k immunopositive interneurons located outside of stratum pyramidale or with parvalbumin, typically found in hippocampal basket cells, suggesting that InsP(3)R1s do not play a role in internal Ca(2+) release in these interneurons. These findings should help to interpret past functional studies and inform future studies examining the characteristics and consequences of InsP(3)R-mediated internal Ca(2+) release and Ca(2+) waves in hippocampal neurons.

Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism.

We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+].

L-Type calcium channels are required for one form of hippocampal mossy fiber LTP.

The requirement of postsynaptic calcium influx via L-type channels for the induction of long-term potentiation (LTP) of mossy fiber input to CA3 pyramidal neurons was tested for two different patterns of stimulation. Two types of LTP-inducing stimuli were used based on the suggestion that one of them, brief high-frequency stimulation (B-HFS), induces LTP postsynaptically, whereas the other pattern, long high-frequency stimulation (L-HFS), induces mossy fiber LTP presynaptically. To test whether or not calcium influx into CA3 pyramidal neurons is necessary for LTP induced by either pattern of stimulation, nimodipine, a L-type calcium channel antagonist, was added during stimulation. In these experiments nimodipine blocked the induction of mossy fiber LTP when B-HFS was given [34 +/- 5% (mean +/- SE) increase in control versus 7 +/- 4% in nimodipine, P < 0.003]; in contrast, nimodipine did not block the induction of LTP with L-HFS (107 +/- 10% in control vs. 80 +/- 9% in nimodipine, P > 0.05). Administration of nimodipine after the induction of LTP had no effect on the expression of LTP. In addition, B- and L-HFS delivered directly to commissural/associational fibers in stratum radiatum failed to induce a N-methyl--aspartate-independent form of LTP, obviating the possibility that the presumed mossy fiber LTP resulted from potentiation of other synapses. Nimodipine had no effect on calcium transients recorded from mossy fiber presynaptic terminals evoked with the B-HFS paradigm but reduced postsynaptic calcium transients. Our results support the hypothesis that induction of mossy fiber LTP by B-HFS is mediated postsynaptically and requires entry of calcium through L-type channels into CA3 neurons.

Spatial distribution of potentiated synapses in hippocampus: dependence on cellular mechanisms and network properties.

Long-term potentiation (LTP) of synaptic transmission, studied intensively in reduced brain preparations such as hippocampal brain slices, is the leading candidate for the cellular/molecular basis of learning and memory. Serious consideration of LTP as underlying information storage in the intact brain, however, requires understanding how LTP can be induced selectively at specific synaptic sites in a neural system when the mechanisms underlying LTP are regulated by other structural and functional properties of the same neural system. In the studies reported here, we tested the hypothesis that different patterns of activity within the same population of entorhinal cortical afferents could lead to a selective potentiation of spatially distinct populations of synapses across different regions of the hippocampus, including those activated multisynaptically. We focused specifically on potentiation of direct, monosynaptic entorhinal input to dentate granule cells, which expresses an NMDA receptor-dependent LTP, and on potentiation of indirect, disynaptic entorhinal input to CA3 pyramidal cells, which is transmitted by the mossy fiber projection of dentate granule cells and expresses an NMDA receptor-independent LTP. The principal findings of these experiments show that lower stimulation frequencies (10-20 Hz) of entorhinal cortical axons selectively induce LTP of mossy fiber input to CA3 transsynaptically via excitation of dentate granule cells, and that patterns of stimulation of that mimic neuronal firing in the entorhinal cortex during endogenous theta rhythm (five-impulse bursts at 200 Hz, interburst intervals of 200 msec) induce LTP both monosynaptically for input to dentate granule cells and transsynaptically for mossy fiber input to CA3.

NMDA receptor-dependent LTD in different subfields of hippocampus in vivo and in vitro.

In simulations with artificial neural networks, efficient information processing and storage has been shown to require that the strength of connections between network elements has the capacity to both increase and decrease in a use-dependent manner. In contrast to long-term potentiation (LTP) of excitatory synaptic transmission, activity-dependent long-term depression (LTD) has been difficult to demonstrate in forebrain in vivo. Theoretical arguments indicate that coincidence of presynaptic excitation and low-magnitude postsynaptic activation are the necessary prerequisites for LTD induction. Here we report that stimulation paradigms which cause 1) sufficient excitation to result in NMDA receptor activation and simultaneously 2) attenuate the level of postsynaptic activation by recruitment of GABAA receptor-mediated inhibition consistently produce LTD of commissural input to area CA1 in the hippocampus of anesthetized adult rats, and of the perforant path input to the dentate gyrus in the hippocampus of anesthetized and unanesthetized adult rabbits. A functionally similar pre- and postsynaptic activation pattern applied to the hippocampal slice preparation by injecting hyperpolarizing current into the postsynaptic cell during NMDA receptor-mediated excitation also was effective in consistently inducing LTD. Results of studies in vitro show that Ca2+ influx through the NMDA channel is necessary for the induction of LTD, and moreover, that NMDA receptors also participate in the expression of LTD. Our findings demonstrate a general mechanism for the implementation of a theoretically derived learning rule in adult forebrain in vivo and in vitro and provide justification for the inclusion of use-dependent decreases of connection weights in formal models of cognitive processing.

Ethanol-induced suppression of hippocampal long-term potentiation is blocked by lesions of the septohippocampal nucleus.

Systemic ethanol increases synaptic inhibition and suppresses long-term potentiation (LTP) in the dentate gyrus of the rat hippocampus. Local application of ethanol directly into the dentate gyrus of anesthetized rats increased the perforant path to dentate feed-forward inhibition, but had no effect on LTP. Local application of ethanol to the medial septum, a subcortical structure with major input to the dentate, increased recurrent inhibition. Selective disruption of septodentate input produced by lesions of the septohippocampal nucleus blocked the effects of systemic ethanol on LTP. These findings are the first to demonstrate that septodentate input is necessary for ethanol to increase recurrent inhibition and suppress LTP in the dentate gyrus and suggest an important role for extrahippocampal modulation of both short- and long-term plasticity in the hippocampus.

Feedforward excitation of the hippocampus by afferents from the entorhinal cortex: redefinition of the role of the trisynaptic pathway.

For the past 3 decades, functional characterizations of the hippocampus have emphasized its intrinsic trisynaptic circuitry, which consists of successive excitatory projections from the entorhinal cortex to the dentate gyrus, from granule cells of the dentate to the CA3/4 pyramidal cell region, and from CA3/4 to the CA1/2 pyramidal cell region. Despite unequivocal anatomical evidence for a monosynaptic projection from entorhinal to CA3 and CA1/2, few in vivo electrophysiological studies of the direct pathway have been reported. In the experiments presented here, we stimulated axons of entorhinal cortical neurons in vivo and recorded evoked single unit and population spike responses in the dentate, CA3, and CA1 of hippocampus, to determine if pyramidal cells are driven primarily via the monosynaptic or trisynaptic pathways. Our results show that neurons within the three subfields of the hippocampus discharge simultaneously in response to input from a given subpopulation of entorhinal cortical neurons and that the initial monosynaptic excitation of pyramidal cells then is followed by weaker excitatory volleys transmitted through the trisynaptic pathway. In addition, we found that responses of CA3 pyramidal cells often precede those of dentate granule cells and that excitation of CA3 and CA1 pyramidal cells can occur in the absence of granule cell excitation. In total, these results argue for a different conceptualization of the functional organization of the hippocampus with respect to the propagation of activity through its intrinsic pathways: input from the entorhinal cortex initiates a two-phase feedforward excitation of pyramidal cells, with the dentate gyrus providing feedforward excitation of CA3, and with both the dentate and CA3 providing feedforward excitation of CA1.