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Previous Article | Next Article
The Journal of Neuroscience, June 15, 2000, 20(12):4379-4388
Opioid Modulation of Recurrent Excitation in the Hippocampal Dentate Gyrus
Gregory W. Terman1, 3, Carrie T. Drake4, Michele L. Simmons2, Teresa A. Milner4, and Charles Chavkin2, 3 Departments of 1 Anesthesiology and 2 Pharmacology and 3 the Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Seattle, Washington 98195-6540, and 4 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
opioid receptor activation inhibits granule cell-mediated excitatory neurotransmission in the hippocampal formation via a decrease in glutamate release from both perforant path and mossy fiber terminals. We now report a third, anatomically and pharmacologically distinct site of such
The
No hilar path excitation was observed in the absence of bicuculline, suggesting a strong GABAA-mediated inhibition of this pathway. However, hilar path activity could be seen after LTP, with or without bicuculline. Thus,
Key words: hippocampus; dentate gyrus;
INTRODUCTION
The importance of the hippocampal formation in learning and memory mechanisms (Holland and Bouton, 1999
) and the role of this region in certain forms of epilepsy (Sloviter, 1999
pyramidal cells in hippocampus proper and granule cells in the dentate gyrus
Previous studies have shown that mossy fiber collaterals within the hilus form a dense plexus of fibers that contain prodynorphin-derived opioids (Zhang and Houser, 1999
Similarly, we and others have reported that granule cell excitation releases dynorphin from granule cell axon terminals (Weisskopf et al., 1993
MATERIALS AND METHODS
Immunocytochemistry. Detailed methods for the anatomical data presented have been described elsewhere (Drake et al., 1994
As in our previous studies (Drake et al., 1994
A modification of the avidin-biotin complex (ABC)-peroxidase technique (Hsu et al., 1981
Sections processed for light microscopy were mounted on gelatin-coated slides, defatted and dehydrated through a graded series of alcohols and xylenes, and coverslipped in DPX (Aldrich). Tissue was examined and photographed on a Nikon Microphot microscope using bright-field and differential interference contrast optics. For electron microscopy, immunolabeled sections were fixed in 2% osmium tetroxide in PB for 1 hr and embedded in EmBed 812 as described previously (Milner and Veznedaroglu, 1992
Electrophysiology. Hippocampal slices (500 µm) were prepared as described previously (Terman et al., 1994
Immediately before placement in the perfusion chamber, knife cuts were made in the slices to anatomically isolate either the hilar pathway or perforant path granule cell afferents. Knife cuts were made with a razor blade fragment held by a hemostat and were guided by the use of a dissecting microscope. The hilar pathway was selectively stimulated in slices containing a knife cut through the molecular layer of the dentate (abutting, but not including, the granule cell layer) to sever the perforant path axons (see Fig. 2B). Similarly, the perforant path was selectively stimulated by making a cut through the hilus, abutting the granule cell layer between the intended locations of the stimulating and recording electrodes (see Fig. 2A).
After at least 1 hr of undisturbed superfusion for equilibration, extracellular recordings were begun in the dentate gyrus granule cell layer of a slice using a glass microelectrode (1-2 µm tip) filled with NaCl (3 mM). Concentric bipolar stimulating electrodes (SNE 100, Kopf Instruments) were placed in the slice at a location relative to the knife cut, which allowed differential stimulation of hilar or perforant path granule cell afferents as detailed for each experiment below. Granule cell population response to a single 100 µA square wave pulse of 0.3 msec duration was measured peak to peak using a digitizing oscilloscope (Tektronix, Beaverton, OR), and the recording electrode was advanced to maximize this response. Stimuli of various intensities (30-500 µA) were then administered in ascending order at 30 sec intervals, and population response amplitudes were recorded. The stimulus intensity that evoked a half-maximal granule cell population spike amplitude (S1/2) was chosen for subsequent test stimuli. S1/2 test pulses were then given at 1 min intervals throughout the experimental period. Before each new tetanic stimulation or drug addition, the stimulus intensity for the test pulse was adjusted to continue evoking a half-maximal (S1/2) response, and at least five baseline test pulses were given. Thus, changes in responsiveness produced by experimental manipulations were based on changes from the baseline measures determined immediately before each manipulation.
Bath-applied drug effects were studied at equilibrium from 15-20 min after addition of drug to the Krebs-bicarbonate perfusate. Perfusion chamber volume measured ~3 ml. Mean granule cell population amplitude responses to five perforant path test pulses (at S1/2) given immediately before drug application were compared with the mean response to five test pulses of the same intensity given beginning 15 min after drug.
Perforant path-granule cell LTP was produced using high-frequency electrical stimulation as previously described (Terman et al., 1994
In the experiments using local application of dynorphin, dynorphin B (100 µM, in Krebs-bicarbonate buffer) was applied separately to either the subgranular zone of the hilus or to the outer half of the molecular layer through a glass pipette connected to a Picospritzer (General Valve, Fairfield, NJ). After a baseline response to electrical stimulation at the S1/2 was established, dynorphin B was pressure-ejected into the tissue (20-40 psi, 50-200 msec duration), and the amplitude of the population response 1 min later was recorded. Raw data were converted to percentage of baseline values for analysis. In some slices, the
In experiments investigating responses to endogenous dynorphin, hilar high-frequency stimulation (HFS) previously found to produce dynorphin release and inhibition of perforant path-granule cell neurotransmission (Wagner et al., 1993
Except for the LTP experiments, all raw data were converted to percentage of baseline values. In the LTP experiments, raw data were converted to percentage potentiation by subtracting 100 from the percentage baseline values. Statistical analysis was performed on transformed data using between-subjects analyses of variance with Neuman-Keuls tests for between group post hoc comparisons (Hays, 1973
Materials. Bicuculline, U69,593, isradipine, and D-2-amino-5-phosphonovalerate (APV) were purchased from Sigma (St. Louis, MO). nBNI and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were purchased from Research Biochemicals International (Natick, MA). All drugs diluted from a concentrated stock solution were added to the perfusate in a 1:1000 dilution.
RESULTS
Anatomical evidence for a direct excitatory granule cell to granule cell pathway
As we and others have previously reported (McLean et al., 1987
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Figure 1. Light and electron microscopic localization of dynorphin-like immunoreactivity in dentate gyrus suggest that mossy fiber collaterals form excitatory synapses with granule cells. A, In the dentate gyrus, dynorphin-li is very dense in mossy fiber collaterals in the plexiform region of the hilus (h) and in mossy fibers as they course to the CA3 region of the hippocampus. Some labeled processes are also present in the granule cell layer (g) and innermost portion of the molecular layer (m). B, Higher magnification of the boxed region in A shows dynorphin-immunolabeled processes in the granule cell layer (g), the inner molecular layer (m), and the subgranular region of the hilus (h). C, Two dynorphin-immunolabeled axon terminals (Dy) at the border between the granule cell and inner molecular layers form asymmetric synaptic specializations (curved arrows) with dendritic shafts (den). The dendritic shaft on the left is continuous with a nearby perikaryon, as indicated by the presence of Golgi apparatus (G) and saccules of rough endoplasmic reticulum (r). (For comparison, rough endoplasmic reticulum is also indicated in an adjacent granule cell perikaryon.) A small axon with dynorphin-li is also present (open arrow). D, A dynorphin-immunolabeled terminal (Dy) forms an asymmetric synapse (curved arrow) with a small dendritic spine (sp) in the inner molecular layer. Scale bars: A, 250 µm; B, 50 µm; C, D, 0.5 µm.
At the ultrastructural level, dynorphin-like immmunolabeling in the granule cell and inner molecular layers was localized to unmyelinated axons and small axon terminals (Fig. 1C,D), resembling mossy fiber collaterals (Claiborne et al., 1986
Electrophysiological evidence of distinct hilar and perforant path granule cell afferents
Stimulation either in the molecular layer (where perforant path and commissural afferents are concentrated) (Fig. 2A,B, electrode 2) or in the hilus (where mossy fiber collaterals, mossy cell axons, and some CA3 pyramidal cell axons provide recurrent excitatory afferents collectively referred to here as the hilar path) (Fig. 2A,B, electrode 3) evoked an extracellularly recorded synaptic response measured in the granule cell layer (data not shown). To better resolve the contributions of the perforant path and the hilar path, specific knife cuts were used (Fig. 2). Selective electrical stimulation of the perforant path, by a stimulating electrode placed in the molecular layer after a knife cut through the hilus, was effective in producing population responses measured in the granule cell layer (Fig. 2A, electrode 2). Surprisingly, a knife cut through the molecular layer, instead of the hilus, did not block the granule cell response to molecular layer stimulation (Fig. 2B, electrode 2). In contrast, molecular layer stimulation in slices with knife cuts through both the molecular layer and hilus did completely block granule cell population responses (data not shown). Thus, the strong granule cell response to molecular layer stimulation after the perforant path (molecular layer) cut suggests that an alternative excitatory input traveling through the hilus was effective in evoking a synaptic response.
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Figure 2. Stimulation site-specific differences between hilar and perforant path granule cell afferent pathways. Scanned cresyl violet-stained guinea pig hippocampal slice with superimposed schematics of the recording electrode (R) in the granule cell layer (G) and several stimulating electrode sites (1-4) in the molecular layer (M) or the hilus (H) of the dentate gyrus. A, The hilar cut slice and representative examples of maximal population responses (peak to peak) to stimulation (at intensities up to 500 µA) at three sites stimulated sequentially as numbered. 1, The stimulation site across the hippocampal fissure from the dentate required 150 µA to achieve a maximal response. 2, Molecular layer stimulus produced a maximal response at 80 µA. 3, Hilar stimulus produced no population spike at a stimulus intensity of 150 µA sufficient to evoke a maximal response without the cut (data not shown), but a response was evoked at 400 µA, presumably by current spread to the perforant path fibers in the molecular layer. B, The molecular layer cut slice and representative examples of maximal population responses to stimulation (at intensities up to 500 µA) at four sites stimulated sequentially as numbered. 1, With the stimulation site across the hippocampal fissure from the dentate gyrus, even a 500 µA stimulus produced no population response. 2, Molecular layer stimulation produced a maximal response at 200 µA. 3, Hilar stimulation produced a maximal response at 150 µA. 4, Molecular layer stimulation distal to a second molecular layer cut produced a maximal response at 200 µA. Calibration: 1 mV, 5 msec.
Granule cell responses to selective activation of the perforant path were nearly unaffected by moving the stimulating electrode across the hippocampal fissure (n = 16) (Fig. 2A, electrode 1). In contrast, hilar path responses were abolished (n = 8) (Fig. 2B, electrode 1) at even very high-stimulus intensities (500 µA). Granule cell responses to selective stimulation of the hilar pathway were only mildly affected by moving the stimulating electrode into the hilus (n = 5) (Fig. 2B, electrode 3). However, such a move in stimulation site decreased granule cell responses to perforant path stimulation (data not shown) unless stimulus intensity was greatly increased (n = 5) (Fig. 2A, electrode 3). Importantly, selective hilar path stimulation by an electrode in the molecular layer distal to the granule cell recording electrode (Fig. 2B, electrode 4) produced no discernable difference in granule cell population responses compared with those elicited by proximal hilar path stimulation (n = 5) (Fig. 2B, electrode 2). These differential responses in molecular layer and hilar cut slices as a function of stimulating electrode placement suggest the validity of our knife cuts in electrophysiologically isolating the hilar and perforant path granule cell afferents. Specifically, the absence of a hilar pathway response to stimulation across the hippocampal fissure suggests that, unlike the perforant path, the hilar path does not originate across the fissure (e.g., in the entorhinal cortex). Moreover, the hilar path responses are bidirectional (i.e., similar responses can be elicited by stimulating distal and proximal to the recording electrode induced responses) (Fig. 2B, electrode 4). This makes the proposed hilar pathway studied here unlikely to simply represent aberrant perforant path fibers coursing through the hilus or granule cell layer en route to terminating in the outer two-thirds of the molecular layer with other perforant path fibers. Thus, it appears that the excitatory hilar path is anatomically and electrophysiologically distinct from the perforant path.
The independence of hilar and perforant path granule cell afferents, as defined by the knife cuts described above, was further examined by inducing LTP in one pathway and observing whether LTP also occurred in the other pathway. A failure to see such cross-potentiation would support the hypothesis that the pathways were distinct. In these studies, we used a single knife cut and two stimulating electrodes (Fig. 3A). LTP was induced (three 100 Hz, 100 msec trains of 0.3 msec, 300 µA pulses given one train every 10 sec) in one pathway with one stimulating electrode, and then granule cell population responses to stimulation in both pathways were assessed in an alternating fashion every 30 sec for 30 min (Fig. 3B). Tetanization (LTP induction) of the hilar path, for instance, produced significantly more LTP 30 min later in the hilar path than in the nontetanized perforant path (Fig. 3B,C). Similarly, tetanization of the perforant path produced significantly more LTP in the perforant path than in the nontetanized hilar path (Fig. 3B,C). These findings are consistent with the hypothesis that the two pathways provide separate afferent inputs to the granule cells. In contrast to both of these findings, control experiments using two separate perforant path stimulating electrodes (Fig. 3D) placed the same distance apart as in the previous experiments demonstrated LTP of responses from both electrodes (cross-potentiation), regardless of which electrode was used to tetanize the slice (Fig. 3C).
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Figure 3. Lack of reciprocal potentiation of hilar and perforant path granule cell inputs. To test the hypothesis that hilar path (HP) and perforant path (PP) afferents independently excite granule cells, LTP of each pathway (n = 6) was induced with a tetanus, and changes were evaluated in the other pathway. Asterisk signifies statistical significance at p < 0.05 level. A, Scanned cresyl violet-stained guinea pig hippocampal slice with a schematic of the recording electrode (R) in the granule cell layer (G), and hilar path (HP) and perforant path (PP) stimulating electrodes in the molecular layer (M) of the dentate gyrus. B, Representative example of granule cell population responses to stimulation of hilar (HP Stim) and perforant (PP Stim) pathways before and 30 min after tetanic stimulation of the hilar path (HP Tetanus). In contrast to the sustained potentiation seen in the tetanized HP pathway (HP Stim), no change was evident in the perforant path (PP Stim). C, Tetanization of the perforant pathway (PP Tetanus) produced significantly more potentiation at 30 min (LTP) in the perforant path (PP Stim) than in the hilar path (HP Stim). Conversely, tetanization of the hilar path (HP Tetanus) produced significantly more LTP in the hilar path (HP Stim) than in the perforant path (PP Stim). In contrast to these results, responses to perforant path stimulation (PP Stim) after LTP induction (PP Tetanus) did not significantly differ from responses to a second stimulating electrode (PP2 Stim) placed in the perforant path (as in D). D, Scanned cresyl violet-stained guinea pig hippocampal slice schematic of the recording electrode (R) in the granule cell layer (G) and two perforant path (PP, PP2) stimulating electrodes in the molecular layer (M) of the dentate gyrus.
Pharmacological properties of hilar and perforant path granule cell afferents
Having provided evidence for the independence of the hilar and perforant path granule cell afferents, we began to investigate their individual neuropharmacological properties. We found, for example, that granule cell excitation by either pathway was unaffected by NMDA receptor blockade produced by bath-applied APV (25 µM) (Fig. 4A). However, blockade of AMPA receptors by CNQX (10 µM) almost completely eliminated any granule cell excitation by either pathway (Fig. 4A). As in the uncut slice, the
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Figure 4.
Hilar dynorphin inhibits hilar path granule cell excitation
To study the sites of action for the inhibitory effects of
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Figure 5. Selective inhibition of perforant path and hilar path neurotransmission by molecular layer and hilar administered dynorphin, respectively. To evaluate the sites of action for
The demonstration that exogenous opioids inhibit excitatory hilar path neurotransmission suggests that endogenous dynorphins present in the mossy fiber collaterals may regulate this path. We have reported that high-frequency stimulation within the hilus (Fig. 6A, electrode SH) can release dynorphin from granule cells (Wagner et al., 1991
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Figure 6. Dynorphin release from perforant path but not hilar path stimulation is dependent on L-type calcium channels. A, Scanned cresyl violet-stained guinea pig hippocampal slice schematic of the recording electrode (R) in the granule cell layer (G) and a stimulating electrode (S) in the molecular layer (M) of the dentate gyrus. A second stimulating electrode was placed in the hilus (SH) to administer high-frequency stimulation to that region (1 sec of 50 Hz, 300 µA, 0.3 msec pulses given six times at 0.5 Hz), a stimulus that we have previously found to release dynorphin in the dentate gyrus (Drake et al., 1994
Site-specific inhibition of neurotransmission and LTP by endogenous
GABA normally inhibits hilar path granule cell excitation
All of the experiments described thus far in the cut slice, as in much of our previous work in the uncut slice, were conducted with bicuculline in the perfusate and thus in the disinhibited slice. We found little difference between normal and disinhibited slices in the maximum amplitude or shape of the granule cell population responses in cut or uncut perforant path stimulated slices (data not shown). However, we have been unable to find even one example thus far of a hilar path-mediated granule cell population response in the guinea pig slice without bicuculline pretreatment, regardless of the intensity of stimulation (Fig. 7A-C). This is perhaps not surprising considering the extensive inhibitory circuitry known to exist in the guinea pig dentate, making LTP and various seizure models (e.g., kindling and pilocarpine) difficult to study in this species without disinhibition. Interestingly, however, we find that the contribution of the hilar pathway to granule cell responses, even in the guinea pig slice without disinhibition, can show considerable plasticity. For example, if during a brief period of GABAA receptor blockade by bicuculline (Fig. 7D) LTP induction takes place in the hilar pathway (Fig. 7E), reestablishment of inhibition (washout of bicuculline) no longer masks the granule cell population response to hilar stimulation (Fig. 7F). These findings suggest that although the hilar path may contribute little to the normal granule cell response in the guinea pig hippocampus (at least in vitro), a brief period of disinhibition via neural, pharmacological, or metabolic means can have long-lasting effects in unmasking hilar path excitatory influences. Importantly,
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Figure 7. Tonic GABAA-mediated inhibition of the hilar pathway is overcome by LTP. Representative oscilloscope traces of a response to stimulation of the hilar pathway (A) at baseline, (B) after bicuculline, (C) after bicuculline washout (45 min), (D) after bicuculline reapplication, (E) after LTP induction, (F) after bicuculline washout again, and (G) after U69,593.
DISCUSSION
In this paper, we have provided anatomical and electrophysiological evidence in the guinea pig for the existence of an excitatory input to the dentate granule cells that is anatomically and pharmacologically distinct from the perforant path. This pathway, coursing through the hilus, can be inhibited by dynorphins released from mossy fiber collaterals in the hilus. These findings give further support for an important role of dynorphin in modulating hippocampal excitability and neuroplasticity in the mammalian brain.
Hilar afferents mediating granule cell excitation
The hilus of the dentate gyrus has become a focus of considerable research on the homeostatic regulation of hippocampal excitability. Our ultrastructural data suggest that there is a direct connection between mossy fiber collaterals and granule cells in the normal guinea pig dentate gyrus. Indirect connections between granule cells via excitatory mossy cells in the hilus have also been demonstrated, although most of these studies have been performed in rats. Granule cell axon collaterals innervate mossy cells in the hilus, and anatomical (Wenzel et al., 1997
Another excitatory input to granule cells that is potentially involved in the hilar pathway is the projection from the supramammillary region of the hypothalamus, which forms excitatory-type synapses on the proximal dendrites and somata of granule cells (Dent et al., 1983
Thus the rich mossy fiber collateral system, running from dentate granule cells through the hilus and in some cases (Fig. 1) forming recurrent excitatory connections to other granule cells, is the likely substrate for the hilar stimulation-induced granule cell excitation studied here. Similar recurrent excitation is already well described in the CA3 (Christian and Dudek, 1988
Dynorphin-sensitive granule cell recurrent excitation is distinct from other dynorphin-sensitive granule cell excitation
This mossy fiber collateral excitatory hilar input to granule cells is anatomically and neurochemically distinct from the perforant path inputs as demonstrated by the differential effects of knife cuts, the independence of LTP, and the site-specific dynorphin-mediated inhibition of the two pathways. Both hilar and perforant path granule cell afferents do release excitatory amino acids and are capable of NMDA-dependent LTP. Clearly, similarities between the mossy fiber terminals in CA3 and those proposed for the hilar path do not extend to NMDA mediation of LTP. The NMDA independence of mossy fiber LTP in CA3 is well described in guinea pigs (Williams and Johnston, 1996
Another difference between perforant path and hilar path activity is the complete suppression of excitatory population responses to hilar stimulation unless the slice is disinhibited. This finding could be attributable to proportionately more inhibitory circuitry than excitatory circuitry remaining intact in vitro or to an extraordinary amount of inhibition present in the guinea pig hippocampus. In either event, it raises the issue of whether the hilar pathway has any importance in normal hippocampal function. In this regard, it is important to note that Hetherington et al. (1994)
Role of
The inhibition of granule cell recurrent excitation may have important physiological implications in seizure pathogenesis. Numerous studies have reported increased mossy fiber collateral sprouting in various animal models of epilepsy (Okazaki et al., 1995
FOOTNOTES Received Aug. 13, 1999; revised March 8, 2000; accepted March 17, 2000.
This work was supported by National Institutes of Health (NIH) Grant DA00266 (G.W.T.), NIH Grant DA04123 (C.C.), an Aaron Diamond postdoctoral fellowship, and NIH Grants DE12738 (C.D.) and DA08259 (T.M.).
Correspondence should be addressed to Dr. Gregory Terman, Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195-6540. E-mail: gwt{at}u.washington.edu.
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