During the course of work on the effects of polarizing currents on the electrical activity of the rat cerebral cortex, we found that prolonged changes in the level of cortical activity could be produced by relatively brief periods of polarizing. This paper describes the after-action of transcortical polarizing current upon the activity evoked by stimulating the forepaw and upon spontaneous firing in cortical neurones. METHODS Experimental AnimalsAbout 200 albino rats of 200-250 g body weight were used. Each rat was anaesthetized with intraperitoneal urethane (360O solution, 0 5 c.c./100 g) and fixed in a rigid head-holder. The cortical surface was exposed by making a trephine hole 4 mm dia. and attaching a polyethylene cup to the skull as described by Bindman, Lippold & Redfearn (1962a) or by drilling 500 , dia. holes with an electric drill. Body temperature was maintained within 0.20 C of a given temperature, usually 350 C, with a 12 V heater driven by an OC 35 transistor, controlled by a thermistor in the rectum.Stimulation and polarization For evoked potential studies, stimuli were delivered at 2 sec intervals to the skin of the forepaw by means of two fine stainless steel needles inserted beneath the skin. The pulse generator gave 200 ,Lsec square waves which were isolated from earth and fed to the preparation by a 1:1 transformer.,The polarizing circuit consisted of a battery across which was connected a potentiometer. A series swamping resistance of 10 MQ was used in order to minimize any effects due to variation in resistance of the electrodes or the preparation. A galvanometer having a deflexion of 4 cm/,uA enabled the current flowing in the circuit to be measured. ElectrodesGlass micro-pipettes, usuallyfilled with 10%/' NaCl solution (and some filled with 1.8 % NaCl and some with 11 O0 KCI), were connected to the pre-amplifier by Ag-AgCl wire. Tip diameters were from 0 5 to 20 , according to requirements. In some experiments non-polarizable wick electrodes or agar gel ones were used for polarizing. * M. R. C. Scholar. 24Physiol. 172

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The prelimbic region of medial frontal cortex in the rat receives a direct input from the hippocampus and this functional connection is essential for aspects of spatial memory. Activity-dependent changes in the effectiveness of synaptic transmission in the medial frontal cortex, namely long-term potentiation (LTP) and long-term depression (LTD) can persist for tens of minutes or hours and may be the basis of learning and memory storage. Glutamatergic activation of ionotropic receptors is required to induce both LTP and LTD. We now present evidence of the involvement of metabotropic glutamate receptors in LTP in isolated slices of frontal cortex. Repetitive bursts of stimulation at theta frequencies (TBS) were applied to layer II, and monosynaptic EPSPs were monitored in layer V neurons of the prelimbic area. TBS was found to be more effective at inducing LTP than tetanic stimulation at 100 Hz and produced LTP that lasted >30 min in 8 out of 14 neurons. Tetanic stimulation at 100 Hz in the presence of the N-methyl--aspartate (NMDA)-antagonist 2-amino-5-phosphonopentanoate (AP5) was reported to be a reliable method of inducing LTD in prelimbic cortex (). However we found that this protocol did not facilitate the induction of LTD. The role of metabotropic glutamate receptors (mGluR) in LTP was assessed by using the selective, broad-spectrum antagonist (R, S)-alpha-methyl-4- carboxyphenylglycine (MCPG). This drug significantly reduced the incidence of LTP after TBS to only 1 of 14 neurons (P < 0.02, chi2 test). The pooled responses to TBS in MCPG showed significantly reduced potentiation [(P < 0.02, analysis of variance (ANOVA)]. The broad-spectrum mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and the selective group I agonist S-3 hydroxyphenylglycine(S-3HPG) both produced membrane depolarization, an increase in number of spikes evoked by depolarizing current pulses, and a reduction in the afterhyperpolarization. Similar effects were produced by these agonists even when synaptic transmission was blocked by use of the gamma-aminobutyric acid-B (GABAB) receptor agonist, 200 microM baclofen, which suggests that group I mGluRs are present on layer V neurons. We conclude that mGluRs participate in the production of LTP in prelimbic cortex, and that this excitatory effect could be mediated by the postsynaptic group I mGluRs.

1. Long-term potentiation (LTP) is an enduring, activity-induced increase in the efficacy of synaptic transmission, which has been considered as a possible neural substrate for learning. Recent experiments have shown that LTP can be induced in hippocampal CA1 neurons when a presynaptic volley is paired repetitively with depolarization of the postsynaptic cell, brought about with intracellularly applied depolarizing current pulses (20, 33). We have repeated these experiments in neocortical neurons, in transverse slices of rat sensorimotor cortex in vitro. 2. Stable intracellular recordings were obtained from 28 neurons (mean resting potential -78 mV, mean spike amplitude 95 mV, mean input resistance 41 M omega) mostly in layers V and VI. Two different afferent pathways were stimulated alternately at 0.2 Hz to evoke subthreshold composite excitatory postsynaptic potentials (EPSPs). One micromolar bicuculline methiodide was added to the bathing medium in most experiments. 3. Repetitive pairing of one afferent volley with a coincident intracellular depolarizing current pulse (100-200 ms long) of a magnitude sufficient to make the neuron fire 6 to 13 action potentials/pulse, gave rise after 30-50 pairings in 4 neurons to a significant enduring increase in the amplitude of the paired EPSP. The increase persisted without decrement for as long as the recording continued (range 15-50 min after the pairing ended) but the amplitude of the unpaired EPSP was unchanged. During the LTP, the membrane potential and the apparent input resistance of the postsynaptic neurons were also unchanged. 4. In two cells a significant prolonged depression of the paired EPSP was induced while the unpaired EPSP was unaffected. Membrane potential and input resistance were not changed. In the remaining 22 cells neither the paired nor the unpaired EPSP was altered. 5. Brief, tetanic stimulation was applied to one afferent pathway in 11 of the neurons in which postsynaptic stimulation had been ineffective. A variety of effects was produced (LTP, depression, or posttetanic potentiation). All the effects of tetanic stimulation were confined to the stimulated pathway. 6. We conclude that LTP can be produced in some neocortical neurons by pairing a presynaptic volley with postsynaptic depolarization, in an experimental paradigm that conforms to Hebb's (17) model of associative conditioning. Depression of the paired EPSP was produced in other cells with the same experimental design.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Long-term depression (LTD) is an activity-dependent reduction in the strength of synaptic transmission that can persist for hours. It is a neural model for processes underlying learning and memory, such as extinction and forgetting. LTD of excitatory postsynaptic potentials (EPSPs) in cells of the CA1 region of hippocampal slices can be induced in an anti-Hebbian paradigm, i.e., by conditioning stimuli that activate the postsynaptic neuron in the absence of evoked synaptic transmission in the test pathway. Past work showed that LTD was not produced consistently in a pharmacologically untreated slice, but it could be induced more reliably when the conditioning stimuli were applied during block of evoked transmitter release. We have now defined further the conditions in which LTD can be obtained using postsynaptic conditioning by investigating 1) whether intracellular conditioning is effective, 2) the requirement for extracellular Ca2+, and 3) the consequences of selective block of glutamate ionotropic receptor subtypes during the conditioning procedure. 2. Intracellular recordings were made from CA1 pyramidal neurons. Test shocks were applied to the stratum radiatum except during conditioning, and the depolarizing slopes and amplitudes of evoked EPSPs were measured. The conditioning procedure activated the postsynaptic neuron either antidromically (via trains of shocks at 100 Hz applied to the axons in the alveus) or intracellularly (via depolarizing pulses of 1.5-3.5 nA). During conditioning, postsynaptic potentials (PSPs) evoked by the conditioning stimuli either were transiently blocked by bathing slices for 5 min in artificial cerebrospinal fluid (CSF) containing a high [Mg2+] or were reduced by glutamate antagonists. 3. When slices were bathed in CSF containing 25 mM Mg2+ and 2 mM Ca2+, evoked PSPs were transiently abolished; conditioning, either by antidromic or intracellular stimulation, always evoked a significant LTD. During the LTD produced by antidromic stimulation, the mean EPSP slope was 52.6 +/- 11.4% (mean +/- SE) of its control at 30-35 min after conditioning (n = 7). The LTD produced by intracellular conditioning was of similar magnitude: the mean EPSP slope was 57.2 +/- 11.6% of its control at 30-35 min postconditioning (n = 7). When slices were bathed in CSF containing 25 mM Mg2+ and 2 mM Ca2+ without conditioning stimuli, there was no LTD (mean EPSP slope 109 +/- 8.1% of its control at 30-35 min after reperfusion with CSF; n = 5).(ABSTRACT TRUNCATED AT 400 WORDS)

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1. Nitric oxide has been implicated in the production of long-term depression (LTD) in the cerebellum and in the production of long-term potentiation (LTP) and LTD in the hippocampus. We now provide evidence of its involvement in the induction of long-term synaptic potentiation in in vitro slices in the cerebral cortex of the rat. 2. Intracellular recordings were made from layer V neurons in the medial frontal cortex, and excitatory synaptic potentials (EPSPs) were evoked by electrical stimulation of layers II/III. Tetanic stimulation of this pathway may induce LTD or LTP or no change at these synapses. First we established experimental conditions under which a long lasting potentiation could be induced with a high incidence (> 60%), namely perfusion of slices with 1 microM bicuculline methiodide, second the use of increased shock duration in the tetanic conditioning stimuli, third and most important the addition of QX-314 to the microelectrode to reduce potassium conductances. Because the potentiation of the mean EPSP slope was significantly greater than the control at 40-min postconditioning, but was declining throughout this period, we refer to it for brevity as LTP, but strictly class it as an LTP-like phenomenon. 3. The nitric oxide (NO) synthase inhibitor interfered with the production of LTP. In the control group of neurons (n = 13) the mean depolarizing slope of the EPSP at 30-min post-conditioning was 142.7 +/- 2% (mean +/- SE) of the prestimulation control.(ABSTRACT TRUNCATED AT 250 WORDS)

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