Long-term depression and depotentiation in the sensorimotor cortex of the freely moving rat

Abstract

Activity-dependent reductions in synaptic efficacy are central components of recent models of cortical learning and memory. Here, we have examined long-term synaptic depression (LTD) and the reversal of long-term potentiation (depotentiation) of field potentials evoked in sensorimotor cortex by stimulation of the white matter in the adult, freely moving rat. Prolonged, low-frequency stimulation (1 Hz for 15 min) was used to induce either depotentiation or LTD. LTD was expressed as a reduction in the amplitude of both monosynaptic and polysynaptic field potential components. Both LTD and depotentiation were reliably induced by stimulation of the ipsilateral white matter. Stimulation of the contralateral neocortex induced only a depotentiation effect, which decayed more rapidly than that induced by ipsilateral stimulation (hours vs days). Although ipsilateral LTD was effectively induced by a single session of low-frequency stimulation, multiple sessions of stimulation, either massed or spaced, induced LTD effects that were larger in magnitude and longer lasting. Previously, we showed that the induction of long-term potentiation in the neocortex of chronic preparations required multiple, spaced stimulation sessions to reach asymptotic levels. Here, we report that LTD also required multiple stimulation sessions to reach asymptotic levels, but massed and spaced patterns of low-frequency stimulation were equally effective.

Fig. 1.

Changes in field potential amplitude evoked in the right sensorimotor cortex by high- and low-frequency stimulation of the homologous contralateral site. Representative field responses are shown for both a control and a potentiated animal (A₁ and A₂), a potentiated and depotentiated animal (B₁ and B₂), and a control and LTD animal (C₁ andC₂). The solid lines represent prestimulation responses, and the dashed lines represent the response after conditioning stimulation had been delivered to the experimental animals. A, High-frequency stimulation caused an enhancement in the repetitive population spike activity (♦) associated with an apparent reduction in the amplitude of the early monosynaptic component (▴) and the enhancement of a longer latency polysynaptic component (▪). B, C,Depotentiation and LTD of field responses evoked in the sensorimotor cortex. Although potentiated (B₁) and control (C₁) responses remain stable in the absence of low-frequency stimulation, depotentiation (B₂) and LTD (C₂) of the late component are induced by the delivery of a single low-frequency (1 Hz, 15 min) train. Stimulation intensity was 795 μA. Calibration: 1 mV, 25 msec.

Fig. 2.

The mean change from baseline amplitude (±SEMs) of the late component in the sensorimotor field potential is shown over days. Stimulation was delivered to the cortex, and the response was recorded in the contralateral homologous site. After 2 d of baseline tests, the LTP animals received 10 d of high-frequency stimulation trains (break in x-axis). Values indicate the change in the late component amplitude relative to the last baseline I–O test. After the induction of LTP, five of the potentiated animals (HFS + LFS), and four of the control animals (LFS) received low-frequency trains (1 Hz, 15 min). I–O measures were collected daily for 2 d and again 1 week later to monitor the longevity of these effects. The LTD effect was not significant, and the depotentiation effect decayed within 24 hr.

Fig. 3.

A comparison of depotentiation effects induced in sensorimotor responses by low-frequency stimulation of either the contralateral homologous site or the ipsilateral white matter.A, Representative sweeps taken from one animal in the ipsilateral group comparing baseline to potentiated and depotentiated responses. LFS caused a decrease in population spike amplitude and number, as well as a decrease in the amplitude of the late component. Calibration: 1 mV, 25 msec. B, C, The mean change from baseline amplitudes (±SEMs) of the early monosynaptic (B) and late polysynaptic (C) components in sensorimotor cortex field potentials are shown here for the contralateral (open squares) and ipsilateral (filled circles) stimulation groups. Values indicate the change in the late component amplitude relative to the last baseline I–O test. Both population spikes and late components were clearly enhanced after 10 d of high-frequency stimulation, and these changes persisted with little decay for the next 7 d. Depotentiation was induced by the delivery of a single low-frequency train (1 Hz, 15 sec) and is reflected as a decrease in amplitude relative to the pre-LFS measures. These effects were only significant for the late component. Although depotentiated responses were still evident after 24 hr in the ipsilateral group, they had recovered back to the potentiated levels in the contralateral group. Stimulation intensity was 250 μA.

Fig. 4.

Multiple low-frequency trains induced a larger and longer lasting LTD effect in ipsilaterally evoked sensorimotor cortex responses than did a single train. A, B, Changes in the amplitude of the early (A) and the late (B) field potential components in a control group and in three groups receiving different patterns of low-frequency stimulation. After three baseline test sessions, experimental groups received either one train (SINGLE TRAIN) or multiple trains. Multiple-train groups received either 10 trains over 10 hr (MASSED-TRAINS) or 10 trains over 10 d (SPACED-TRAINS). Control animals did not receive low-frequency stimulation. Values indicate the change in the late component amplitude relative to the last baseline I–O test. A substantial LTD effect was found in all experimental groups, and the multiple-train stimulation produced the largest and longest lasting effects. The stimulation intensity was 250 μA. C, D,Representative sweeps from animals in the single-train (C) and spaced-trains (D) LTD groups. The baseline responses are compared to the responses evoked 2 weeks after the induction of LTD. Calibration: 1 mV, 25 msec.

Fig. 5.

Multiple sessions augment the LTD effect observed after the first session of low-frequency (1 Hz for 15 min) stimulation.A, Representative sweeps from an animal in the spaced-trains group comparing the first session and 10th session LTD effect to the last baseline response. Calibration: 1 mV, 25 msec.B, C, Changes in response amplitudes for the early monosynaptic (B) and longer latency polysynaptic (C) components monitored during LTD induction in the multiple train groups. Trains were delivered either hourly (MASSED-TRAINS) or daily (SPACED-TRAINS). I–O tests were recorded both before and after each train in the spaced trains groups, so that the decay of the LTD effect could be observed for each 24 hr poststimulation period. The final point in the graph shows response amplitudes 24 hr after the last low-frequency train. Similar amounts of LTD were observed for both spaced and massed groups.