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Heterosynaptic long-term depression in the hippocampus
J Physiology (Paris) (1996) 90, 165-166 OElsevier, Paris
Heterosynaptic long-term depression in the hippocampus M Scanziani’, RA Nicollb,c, RC Malenkaa3 b* aDepartment of Psychiatry, Langley Porter Psychiatr?, Institute; hDepatiment qf Physiology, and ‘Department qf Cell&r and Molecular Pharmacology, University of California. 401 Pamassus Avenue, Box 0984. San Francisco, CA 94143-0984. USA
Summary - Heterosynaptic long-term depression (hetLTD) at one input can be induced by applying a conditioning stimulus to an adjacent set of synapses. In hippocampal CA1 pyramidal cells, our results suggest that hetLTD is triggered by an extracellular diffusible factor that is released following tetanic activation of NMDA receptors. This hetLTD occludes with homosynaptic LTD suggesting common underlying mechanisms. asynchrony
I heterosynaptic
plasticity I long-term depression
I hippocampal
Activity-dependent heterosynaptic decreases in synaptic strength may be used both for information storage and the modification of neural circuitry. Recently, we (Scanziani et al, 1996) examined the mechanisms of one form of heterosynaptic long-term depression (hetI_TD) in the CA1 region of young (2-4 weeks) hippocampal slices. Tetanic stimulation (100 Hz, 1 s given four times 20 s apart) of one input caused a hetLTD (-15 f. 2%, n = 20) of an independent input that remained stable at 60 min. This hetLTD was reversibly blocked by the NMDA receptor antagonists D-APV (25-50 PM) (fig 1) and CPP (20 @M) but was unaffected by the L-type Ca2’ channel blocker nimodipine (50 l.tM). To examine the potential role of other classes of Ca2+ channel, cells were voltage clamped at positive potentials (+ 40 mV) so that during the tetanus the envelope of synaptic current was outward and therefore could not activate voltage-dependent Ca2+ channels. Under these conditions, robust hetl_TD was still elicited (n = 6). These results suggest that a rise in postsynaptic Ca” may not be required for this form of hetLTD. To examine this possibility directly, cells were loaded with the Ca*’ chelator, BAPTA (10 r&I). This manipulation completely blocked LTP in the tetanized input but hetLTD remained and was actually larger than that recorded in interleaved control cells (-31 + 3%, n = 8 versus -12 f l%, IZ= 5). As previously reported (Mulkey and Male&a, 1992) we also observed that homosynaptic LTD was blocked by loading cells with BAPTA. Indeed this differential effect of BAPTA on hetLTD and homosynaptic LTD could be demonstrated in the same cell. To determine the location of the NMDA receptors that are required to generate hetLTD, we took advant-
*Correspondence
and reprints
slice I calcium channel I phosphatase
inhibitor
age of the properties of the use-dependent NMDA receptor antagonist, MK-801. In one set of experiments, we blocked all of the NMDA receptors activated by one input by applying a series of tetani to this input in the presence of MK-801. The MK-801 was then washed out for 40-50 min at which point tetanization of a neighboring input still produced hetLTD in the input in which NMDA receptors had been blocked (n = 5). This result indicates that NMDA receptors on the recipient input expressing hetLTD are not required for eliciting hetLTD. To determine whether NMDA receptors on the cell expressing hetLTD actually need to be activated to generate hetLTD, cells were held at positive potentials while stimulating an input at low frequencies in the presence of MK-801 until synaptic NMDA receptor mediated currents were completely blocked. This manipulation results in the blockade of NMDA receptors on the depolarized cell but not on neighboring cells. Tetanizing this input still elicited hetLTD on a neighboring independent input (n = 4) and interestingly also caused a homosynaptic LID, rather than LTP. Taken together, these results suggest that, unlike homosynaptic LTD, this form of hetLTD does not require activation of NMDA receptors or a rise in postsynaptic Ca” in the cell expressing the plasticity. Nevertheless, two results suggest that the two forms of LTD appear to share some common mechanisms. First, prior saturation of homosynaptic LTD prevents the subsequent expression of hetLTD (n = 4). Second, loading cells with the protein phosphatase inhibitor microcystin-LR (10 pM) blocked hetLTD (n = 7). In contrast, intracellular application of the calcineurin inhibitor FK506 (50 yM) failed to affect hetLTD (n = 5), a result consistent with the suggestion that hetLTD does not require increases in postsynaptic Ca” in the cells expressing hetLTD. Based on these results, our current working hypothesis is that tetanic activation of NMDA receptors can cause the release of a diffusible substance that generates
166
I31
Al
5ms
D-APV
0
Time (min)
10
50L1 -10
, 0
10
20 -10 0 Time (min)
10
20
30
40
Fig 1. Induction of heterosynaptic
LTD (hetLTD) requires activation of NMDA receptors. A.l. Example of hetLTD induced by tetanizing a second. independent pathway at the time indicated by the arrow. The traces represent average field EPSPs recorded immediately before and 20 min after the induction protocol. The same traces are shown superimposed , with an expanded time scale, on the right. A.2. Summary graph (n = 20) showing both the tetanized pathway (open triangles, right ordinate) and the heterosynaptic pathway (tilled circles, left ordinate). B-1. Bath perfusion of D-APV (25-50 @vl) reversibly blocked the induction of hetLTD. B.2. Summary graph (n = 5) of the effects of D-APV (reproduced from Scanziani rr al, 1996).
LTD on neighboring cells. This substance may work by activating protein phosphatase 1 in a Ca” indenendent manner. The involvement of a diffusible substance may help to ensure that under appropriate conditions, hetLTD is widespread. HetLTD has also been observed in neocortical urenarations Castro-Alamancos et al, 1995) and thus it is interesting to speculate about the possible role of this type of he&ID in the development and modification of local cortical networks. I
I
1
f
References Castro-Alamancos MA, Donoghue JP, Connors BW (1995) Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex. J Neurosci 15, 53245333 Mulkey RM. Malenka RC (1992) Mechanisms underlying induction of homosvnaptic long-term depression in area CA1 of hiopo.. campus. hreuron 9,9%7-975 . Scanziani M. Malenka RC, Nicoll RA (1996)Role of intercellular interactions in heterosynaptic long-term depression. Nntttre 380. 446-450 . _ .
Heterosynaptic long-term depression in the hippocampus M Scanziani’, RA Nicollb,c, RC Malenkaa3 b* aDepartment of Psychiatry, Langley Porter Psychiatr?, Institute; hDepatiment qf Physiology, and ‘Department qf Cell&r and Molecular Pharmacology, University of California. 401 Pamassus Avenue, Box 0984. San Francisco, CA 94143-0984. USA
Summary - Heterosynaptic long-term depression (hetLTD) at one input can be induced by applying a conditioning stimulus to an adjacent set of synapses. In hippocampal CA1 pyramidal cells, our results suggest that hetLTD is triggered by an extracellular diffusible factor that is released following tetanic activation of NMDA receptors. This hetLTD occludes with homosynaptic LTD suggesting common underlying mechanisms. asynchrony
I heterosynaptic
plasticity I long-term depression
I hippocampal
Activity-dependent heterosynaptic decreases in synaptic strength may be used both for information storage and the modification of neural circuitry. Recently, we (Scanziani et al, 1996) examined the mechanisms of one form of heterosynaptic long-term depression (hetI_TD) in the CA1 region of young (2-4 weeks) hippocampal slices. Tetanic stimulation (100 Hz, 1 s given four times 20 s apart) of one input caused a hetLTD (-15 f. 2%, n = 20) of an independent input that remained stable at 60 min. This hetLTD was reversibly blocked by the NMDA receptor antagonists D-APV (25-50 PM) (fig 1) and CPP (20 @M) but was unaffected by the L-type Ca2’ channel blocker nimodipine (50 l.tM). To examine the potential role of other classes of Ca2+ channel, cells were voltage clamped at positive potentials (+ 40 mV) so that during the tetanus the envelope of synaptic current was outward and therefore could not activate voltage-dependent Ca2+ channels. Under these conditions, robust hetl_TD was still elicited (n = 6). These results suggest that a rise in postsynaptic Ca” may not be required for this form of hetLTD. To examine this possibility directly, cells were loaded with the Ca*’ chelator, BAPTA (10 r&I). This manipulation completely blocked LTP in the tetanized input but hetLTD remained and was actually larger than that recorded in interleaved control cells (-31 + 3%, n = 8 versus -12 f l%, IZ= 5). As previously reported (Mulkey and Male&a, 1992) we also observed that homosynaptic LTD was blocked by loading cells with BAPTA. Indeed this differential effect of BAPTA on hetLTD and homosynaptic LTD could be demonstrated in the same cell. To determine the location of the NMDA receptors that are required to generate hetLTD, we took advant-
*Correspondence
and reprints
slice I calcium channel I phosphatase
inhibitor
age of the properties of the use-dependent NMDA receptor antagonist, MK-801. In one set of experiments, we blocked all of the NMDA receptors activated by one input by applying a series of tetani to this input in the presence of MK-801. The MK-801 was then washed out for 40-50 min at which point tetanization of a neighboring input still produced hetLTD in the input in which NMDA receptors had been blocked (n = 5). This result indicates that NMDA receptors on the recipient input expressing hetLTD are not required for eliciting hetLTD. To determine whether NMDA receptors on the cell expressing hetLTD actually need to be activated to generate hetLTD, cells were held at positive potentials while stimulating an input at low frequencies in the presence of MK-801 until synaptic NMDA receptor mediated currents were completely blocked. This manipulation results in the blockade of NMDA receptors on the depolarized cell but not on neighboring cells. Tetanizing this input still elicited hetLTD on a neighboring independent input (n = 4) and interestingly also caused a homosynaptic LID, rather than LTP. Taken together, these results suggest that, unlike homosynaptic LTD, this form of hetLTD does not require activation of NMDA receptors or a rise in postsynaptic Ca” in the cell expressing the plasticity. Nevertheless, two results suggest that the two forms of LTD appear to share some common mechanisms. First, prior saturation of homosynaptic LTD prevents the subsequent expression of hetLTD (n = 4). Second, loading cells with the protein phosphatase inhibitor microcystin-LR (10 pM) blocked hetLTD (n = 7). In contrast, intracellular application of the calcineurin inhibitor FK506 (50 yM) failed to affect hetLTD (n = 5), a result consistent with the suggestion that hetLTD does not require increases in postsynaptic Ca” in the cells expressing hetLTD. Based on these results, our current working hypothesis is that tetanic activation of NMDA receptors can cause the release of a diffusible substance that generates
166
I31
Al
5ms
D-APV
0
Time (min)
10
50L1 -10
, 0
10
20 -10 0 Time (min)
10
20
30
40
Fig 1. Induction of heterosynaptic
LTD (hetLTD) requires activation of NMDA receptors. A.l. Example of hetLTD induced by tetanizing a second. independent pathway at the time indicated by the arrow. The traces represent average field EPSPs recorded immediately before and 20 min after the induction protocol. The same traces are shown superimposed , with an expanded time scale, on the right. A.2. Summary graph (n = 20) showing both the tetanized pathway (open triangles, right ordinate) and the heterosynaptic pathway (tilled circles, left ordinate). B-1. Bath perfusion of D-APV (25-50 @vl) reversibly blocked the induction of hetLTD. B.2. Summary graph (n = 5) of the effects of D-APV (reproduced from Scanziani rr al, 1996).
LTD on neighboring cells. This substance may work by activating protein phosphatase 1 in a Ca” indenendent manner. The involvement of a diffusible substance may help to ensure that under appropriate conditions, hetLTD is widespread. HetLTD has also been observed in neocortical urenarations Castro-Alamancos et al, 1995) and thus it is interesting to speculate about the possible role of this type of he&ID in the development and modification of local cortical networks. I
I
1
f
References Castro-Alamancos MA, Donoghue JP, Connors BW (1995) Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex. J Neurosci 15, 53245333 Mulkey RM. Malenka RC (1992) Mechanisms underlying induction of homosvnaptic long-term depression in area CA1 of hiopo.. campus. hreuron 9,9%7-975 . Scanziani M. Malenka RC, Nicoll RA (1996)Role of intercellular interactions in heterosynaptic long-term depression. Nntttre 380. 446-450 . _ .