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Feedforward Excitation of the Hippocampus by Afferents from the Entorhinal Cortex: Redefinition of the Role of the Trisynaptic Pathway MARK F

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Feedforward Excitation of the Hippocampus by Afferents from the Entorhinal Cortex: Redefinition of the Role of the Trisynaptic Pathway MARK F Proc. Natl. Acad. Sci. USA Vol. 87, pp. 5832-5836, August 1990 Neurobiology Feedforward excitation of the hippocampus by afferents from the entorhinal cortex: Redefinition of the role of the trisynaptic pathway MARK F. YECKEL* AND THEODORE W. BERGER*tt Departments of *Behavioral Neuroscience and tPsychiatry, University of Pittsburgh, Pittsburgh, PA Communicated by Richard F. Thompson, April 9, 1990 (received for review September 26, 1989) ABSTRACT For the past 3 decades, functional character- hippocampal cell groups (see Fig. 1). Although evidence for izations of the hippocampus have emphasized its intrinsic the functional viability of monosynaptic entorhinal input to trisynaptic circuitry, which consists of successive excitatory pyramidal neurons has been provided (9-11), the relative projections from the entorhinal cortex to the dentate gyrus, strengths ofthe monosynaptic and trisynaptic pathways have from granule cells of the dentate to the CA3/4 pyramidal cell gone untested. At least one investigation has questioned the region, and from CA3/4 to the CA1/2 pyramidal cell region. sufficiency ofmonosynaptic entorhinal input for suprathresh- Despite unequivocal anatomical evidence for a monosynaptic old activation of pyramidal neurons (5). Other studies using projection from entorhinal to CA3 and CA1/2, few in vivo the in vitro hippocampal slice have examined pyramidal cell electrophysiological studies of the direct pathway have been responses to electrical stimulation of monosynaptic afferents reported. In the experiments presented here, we stimulated within the dendritic region containing terminals of entorhinal axons of entorhinal cortical neurons in vivo and recorded axons (12). The entorhinal pathway cannot be activated evoked single unit and population spike responses in the selectively in an in vitro preparation, however, because dentate, CA3, and CAl of hippocampus, to determine if afferents from other brain regions terminate within the same pyramidal cells are driven primarily via the monosynaptic or dendritic zone (13-15). More importantly, it is not possible to trisynaptic pathways. Our results show that neurons within the establish with an in vitro preparation ifa given subpopulation three subfields ofthe hippocampus discharge simultaneously in of hippocampal pyramidal neurons receives entorhinal input response to input from a given subpopulation of entorhinal primarily via monosynaptic or multisynaptic pathways. cortical neurons and that the initial monosynaptic excitation of Thus, the extent to which the trisynaptic pathway represents pyramidal cells then is followed by weaker excitatory volleys a fundamental constraint on multisynaptic transmission transmitted through the trisynaptic pathway. In addition, we through the hippocampus remains to be determined. In the found that responses of CA3 pyramidal cells often precede experiments reported here, we used electrophysiological those of dentate granule cells and that excitation of CA3 and methods to compare the latency and strength of entorhinal CAl pyramidal cells can occur in the absence of granule cell input to CA3 and CA1 pyramidal neurons with the latency excitation. In total, these results argue for a different concep- and strength of input to dentate granule cells from the same tualization of the functional organization of the hippocampus population of entorhinal fibers. with respect to the propagation of activity through its intrinsic pathways: input from the entorhinal cortex initiates a two- MATERIALS AND METHODS phase feedforward excitation of pyramidal cells, with the Male New Zealand White rabbits (n = 45) were anesthetized dentate gyrus providing feedforward excitation of CA3, and continuously with halothane. Bipolar stimulating electrodes with both the dentate and CA3 providing feedforward excita- were positioned stereotaxically into one or two of the fol- tion of CAL. lowing: (i) perforant path fibers ofthe angular bundle, (ii) the ipsilateral stratum radiatum of CA3 or CAl, (iii) the hilus The hippocampus is composed of three major subdivisions: ipsilateral to the perforant path stimulating electrode, (iv) the the dentate gyrus and the CA3/4 and CA1/2 pyramidal cell hilus contralateral to the perforant path stimulating electrode. regions (1). Connectivity between the three cell fields is Stimulation impulses (0.1-0.2 ms) were delivered by using unidirectional, with granule cells of the dentate gyrus pro- constant low frequencies (0.2 Hz or less); pairs and triplets of jecting to the CA3/4 pyramidal neurons, which in turn project impulses with interimpulse intervals that varied from 10 to to CA1/2 pyramidal cells (2). Excitatory perforant path fibers 200 ms; and trains of 10-20 impulses with interimpulse arising from the entorhinal cortex are the major afferents to intervals corresponding to 5-200 Hz. the dentate (3, 4), and numerous studies have demonstrated Extracellular recording electrodes (insulated stainless that activation of the perforant path can initiate a sequential steel) had tip impedances of 1-2 Mfl when tested using 135 excitation of dentate granule, CA3/4 pyramidal, and CA1/2 Hz in vitro. Recording electrodes were positioned stereo- pyramidal cell populations (5, 6). Serial propagation through taxically throughout the dorsal hippocampus. Recording and this "trisynaptic pathway" has become regarded as the stimulation sites were verified by a Prussian blue reaction for fundamental characteristic of intrinsic hippocampal physiol- iron deposits. In some experiments, the selective GABAA ogy (7). agonist muscimol (500 ,uM) was delivered with a micropres- In contrast to physiological evidence for the trisynaptic sure ejection system (15-ms impulses; 5-15 psi; 1 psi = 6.9 pathway, results from anatomical investigations consistently kPa) simultaneously during recording. Evoked field poten- have shown that the entorhinal cortex innervates each of the tials were band-pass filtered using low- and high-frequency dentate, CA3, and CA1/2 regions (8), suggesting simulta- limits of 10 Hz and 10 kHz, respectively. Unitary spike neous rather than sequential excitation of the three intrinsic Abbreviation: EPSP, excitatory postsynaptic potential. The publication costs ofthis article were defrayed in part by page charge to whom reprint requests should be addressed at: 465 Crawford payment. This article must therefore be hereby marked "advertisement" Hall, Department of Behavioral Neuroscience, University of Pitts- in accordance with 18 U.S.C. §1734 solely to indicate this fact. burgh, Pittsburgh, PA 15260. 5832 Downloaded by guest on September 27, 2021 Neurobiology: Yeckel and Berger Proc. Natl. Acad. Sci. USA 87 (1990) 5833 events evoked from single cells were differentiated from field latencies of 4-7 ms (Fig. 2 A and B), consistent with mono- potentials by using low- and high-frequency limits of 100- synaptic input from the direct entorhinal projection. This 1000 Hz and 6 kHz, respectively. interpretation was supported by several findings. Among those are the results oflaminar analyses, in which a recording RESULTS electrode was lowered progressively from the cell body layer of CA1 to the cell body layer of CA3, parallel to the dendritic Multisynaptic Excitation of CA3 and CAl Pyramidal Neu- axes, during low-frequency stimulation ofthe angular bundle. rons Via the Trisynaptic Pathway. Stimulation of perforant When the recording electrode was located in the cell body path fibers resulted in the sequential excitation of dentate layer of CAl, stimulation evoked a short-latency positive- granule, CA3 pyramidal, and CAl pyramidal cells charac- going field potential-i.e., a population excitatory postsyn- teristic of the trisynaptic pathway. Latencies to population aptic potential (EPSP) consistent with a current sink gener- and single cell responses were progressively longer within ated by synaptic input terminating in the apical dendrites (3, each of the three hippocampal subfields: 4-6 ms for granule 4). Ifsufficient stimulation current was used, a negative-going cells, 9-13 ms for CA3 neurons, and 16-21 ms for CA1 cells. population spike was superimposed on the population EPSP; Responses ofgranule cells satisfied all established criteria (3, the presence of evoked action potentials with latencies cor- 4) for monosynaptic activation (Fig. 1B). The longer latency responding to that of the negative wave confirmed its inter- excitations of CA3 and CA1 neurons were consistent with pretation as a population spike (4, 17). When the recording multisynaptic activation, as they did not follow more than the electrode was moved into the apical dendritic region, the first few impulses of trains of continuous stimulation deliv- population EPSP reversed in polarity (without a change in ered at frequencies of >25 Hz. Latencies of pyramidal cell latency) to become negative going, indicating its generation discharge also were consistent with the cumulative mono- in the apical dendrites. Increasing stimulation intensity re- synaptic latencies for each of the individual pathways com- sulted in greater amplitude and onset slope of the population prising the trisynaptic circuit: 4-6 ms for perforant pathway EPSP without decreasing onset latency, supporting an inter- input to granule cells, 4-8 ms for activation ofCA3 by mossy pretation of the negativity as a dendritic response to mono- fiber stimulation, and 4-6 ms for responses of CA1 cells synaptic input. evoked by Schaffer collateral stimulation. These observa- The population EPSP reached maximum amplitude in the
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