Long-term Potentiation at Temporoammonic Path-CA1 Synapses in Freely Moving Rats.

Hippocampal area CA1 receives direct entorhinal layer III input via the temporoammonic path (TAP) and recent studies implicate TAP-CA1 synapses are important for some aspects of hippocampal memory function. Nonetheless, as few studies have examined TAP-CA1 synaptic plasticity in vivo, the induction and longevity of TAP-CA1 long-term potentiation (LTP) has not been fully characterized. We analyzed CA1 responses following stimulation of the medial aspect of the angular bundle and investigated LTP at medial temporoammonic path (mTAP)-CA1 synapses in freely moving rats. We demonstrate monosynaptic mTAP-CA1 responses can be isolated in vivo as evidenced by observations of independent current sinks in the stratum lacunosum moleculare of both areas CA1 and CA3 following angular bundle stimulation. Contrasting prior indications that TAP input rarely elicits CA1 discharge, we observed mTAP-CA1 responses that appeared to contain putative population spikes in 40% of our behaving animals. Theta burst high frequency stimulation of mTAP afferents resulted in an input specific and N-methyl-D-aspartate (NMDA) receptor-dependent LTP of mTAP-CA1 responses in behaving animals. LTP of mTAP-CA1 responses decayed as a function of two exponential decay curves with time constants (τ) of 2.7 and 148 days to decay 63.2% of maximal LTP. In contrast, mTAP-CA1 population spike potentiation longevity demonstrated a τ of 9.6 days. To our knowledge, these studies provide the first description of mTAP-CA1 LTP longevity in vivo. These data indicate TAP input to area CA1 is a physiologically relevant afferent system that displays robust synaptic plasticity.

Low-frequency stimulation induces long-term depression and slow onset long-term potentiation at perforant path-dentate gyrus synapses in vivo.

The expression of homosynaptic long-term depression (LTD) is thought to mediate a crucial role in sustaining memory function. Our in vivo investigations of LTD expression at lateral (LPP) and medial perforant path (MPP) synapses in the dentate gyrus (DG) corroborate prior demonstrations that PP-DG LTD is difficult to induce in intact animals. In freely moving animals, LTD expression occurred inconsistently among LPP-DG and MPP-DG responses. Interestingly, following acute electrode implantation in anesthetized rats, low-frequency stimulation (LFS; 900 pulses, 1 Hz) promotes slow-onset LTP at both MPP-DG and LPP-DG synapses that utilize distinct induction mechanisms. Systemic administration of the N-methyl-d-aspartate (NMDA) receptor antagonist (+/-)-cyclopiperidine-6-piperiperenzine (CPP; 10 mg/kg) 90 min before LFS selectively blocked MPP-DG but not LPP-DG slow onset LTP, suggesting MPP-DG synapses express a NMDA receptor-dependent slow onset LTP whereas LPP-DG slow onset LTP induction is NMDA receptor independent. In experiments where paired-pulse LFS (900 paired pulses, 200-ms paired-pulse interval) was used to induce LTD, paired-pulse LFS of the LPP resulted in rapid onset LTP of DG responses, whereas paired-pulse LFS of the MPP induced slow onset LTP of DG responses. Although LTD observations were very rare following acute electrode implantation in anesthetized rats, LPP-DG LTD was demonstrated in some anesthetized rats with previously implanted electrodes. Together, our data indicate in vivo PP-DG LTD expression is an inconsistent phenomenon that is primarily observed in recovered animals, suggesting perturbation of the dentate through surgery-related tissue trauma influences both LTD incidence and LTP induction at PP-DG synapses in vivo.

Modulation of CA3 afferent inputs by novelty and theta rhythm.

Models of hippocampal function suggest that the modulation of CA3 afferent input during theta rhythm allows for a rapid alternation between encoding and retrieval states, with each phase enhancing either extrinsic or intrinsic CA3 afferents, favoring either encoding or retrieval, respectively. Here, we show that during the initial exploration of a novel environment by rats, intrinsic CA3-CA3 synaptic inputs are attenuated on CA3 theta peaks, favoring extrinsic CA3 inputs, whereas extrinsic perforant path-CA3 synaptic inputs are attenuated on CA3 theta troughs, favoring intrinsic CA3 inputs. This modulation is absent when animals are re-exposed to the same environment 2 or 48 h later and thus habituates with familiarity, suggesting a process involved in learning. Modulation of CA3 synaptic inputs during novelty was blocked by atropine at a dose that blocks type 2 theta rhythm. Re-exposure to the same novel environment 48 h later in the absence of atropine did not result in habituation, but instead modulated CA3 synaptic responses as though the environment were novel and explored for the first time. The NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), administered in a dose that blocks long-term potentiation induction, did not alter CA3 synaptic modulation during initial exploration. However, like atropine, CPP blocked the habituation of synaptic modulation normally observed with re-exposure, as though the environment were novel and explored for the first time. Thus, as predicted theoretically, recurrent and cortical CA3 afferents are differentially modulated during phases of theta rhythm. This modulation is atropine sensitive and habituates in an NMDA receptor-dependent manner, suggesting an NMDA receptor-dependent process that, in conjunction with theta rhythm, contributes to encoding of novel information in the hippocampus.

NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay.

Although long-term potentiation (LTP) is long-lasting, it is not permanent and decays within weeks after its induction. Little is known about the processes underlying this decay. Here we assessed the contribution of synaptic activity to LTP decay by determining the effect of the competitive NMDA receptor antagonist CPP on the decay of perforant path-dentate LTP. CPP blocked decay over a one-week period when administered daily following the induction of LTP, and blocked decay of the late, protein-synthesis-dependent phase of LTP when administered two days after LTP induction. CPP administered for a five-day period following spatial memory training enhanced subsequent memory retention. These data suggest that LTP is normally a persistent process that is actively reversed by NMDA receptor activation, and that both the early and late phases of LTP are dynamic processes regulated by NMDA receptors. These data also support the view that LTP is involved in maintaining spatial memory.