Hippocampal Network Activity is Transiently Altered by Induction of Long-Term Potentiation in the Dentate Gyrus of Freely Behaving Rats

A role for oscillatory activity in hippocampal neuronal networks has been proposed in sensory encoding, cognitive functions and synaptic plasticity. In the hippocampus, theta (5–10 Hz) and gamma (30–100 Hz) oscillations may provide a mechanism for temporal encoding of information, and the basis for formation and retrieval of memory traces. Long-term potentiation (LTP) of synaptic transmission, a candidate cellular model of synaptic information storage, is typically induced by high-frequency tetanisation (HFT) of afferent pathways. Taking into account the role of oscillatory activity in the processing of information, dynamic changes may occur in hippocampal network activity in the period during HFT and/or soon after it. These changes in rhythmic activity may determine or, at least, contribute to successful potentiation and, in general, to formation of memory. We have found that short-term potentiation (STP) and LTP as well LTP-failure are characterised with different profiles of changes in theta and gamma frequencies. Potentiation of synaptic transmission was associated with a significant increase in the relative theta power and mean amplitude of theta cycles in the period encompassing 300 seconds after HFT. Where LTP or STP, but not failure of potentiation, occurred, this facilitation of theta was accompanied by transient increases in gamma power and in the mean amplitude of gamma oscillations within a single theta cycle. Our data support that specific, correlated changes in these parameters are associated with successful synaptic potentiation. These findings suggest that changes in theta-gamma activity associated with induction of LTP may enable synaptic information storage in the hippocampus

Visual Cortex Plasticity Evokes Excitatory Alterations in the Hippocampus

The integration of episodic sequences in the hippocampus is believed to occur during theta rhythm episodes, when cortico-hippocampal dialog results in reconfiguration of neuronal assemblies. As the visual cortex (VC) is a major source of sensory information to the hippocampus, information processing in the cortex may affect hippocampal network oscillations, facilitating the induction of synaptic modifications. We investigated to what degree the field activity in the primary VC, elicited by sensory or electrical stimulation, correlates with hippocampal oscillatory and synaptic responsiveness, in freely behaving adult rats. We found that the spectral power of theta rhythm (4–10 Hz) in the dentate gyrus (DG), increases in parallel with high-frequency oscillations in layer 2/3 of the VC and that this correlation depends on the degree of exploratory activity. When we mimic robust thalamocortical activity by theta-burst application to dorsal lateral geniculate nucleus, a hippocampal theta increase occurs, followed by a persistent potentiation of the DG granule field population spike. Furthermore, the potentiation of DG neuronal excitability tightly correlates with the concurrently occurring VC plasticity. The concurrent enhancement of VC and DG activity is also combined with a highly negative synchronization between hippocampal and cortical low-frequency oscillations. Exploration of familiar environment decreases the degree of this synchrony. Our data propose that novel visual information can induce high-power fluctuations in intrinsic excitability for both VC and hippocampus, potent enough to induce experience-dependent modulation of cortico-hippocampal connections. This interaction may comprise one of the endogenous triggers for long-term synaptic plasticity in the hippocampus

Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning

Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of these receptors in persistent (>24h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an important role for dopamine acting on D1/D5 receptors in the support of long-lasting and learning-related forms of synaptic plasticity at MF-CA3 synapses and provide further evidence for an important neuromodulatory role for this receptor in experience-dependent synaptic encoding in the hippocampal subfields

Strain-Dependent Variations in Spatial Learning and in Hippocampal Synaptic Plasticity in the Dentate Gyrus Of Freely Behaving Rats

Hippocampal synaptic plasticity is believed to comprise the cellular basis for spatial learning. Strain-dependent differences in synaptic plasticity in the CA1 region have been reported. However, it is not known whether these differences extend to other synapses within the trisynaptic circuit, although there is evidence for morphological variations within that path. We investigated whether Wistar and Hooded Lister (HL) rat strains express differences in synaptic plasticity in the dentate gyrus in vivo. We also explored whether they exhibit differences in the ability to engage in spatial learning in an eight-arm radial maze. Basal synaptic transmission was stable over a 24-h period in both rat strains, and the input–output relationship of both strains was not significantly different. Paired-pulse analysis revealed significantly less paired-pulse facilitation in the HL strain when pulses were given 40–100 ms apart. Low frequency stimulation at 1 Hz evoked long-term depression (>24 h) in Wistar and short-term depression (<2 h) in HL rats; 200 Hz stimulation induced long-term potentiation (>24 h) in Wistar, and a transient, significantly smaller potentiation (<1 h) in HL rats, suggesting that HL rats have higher thresholds for expression of persistent synaptic plasticity. Training for 10 days in an eight-arm radial maze revealed that HL rats master the working memory task faster than Wistar rats, although both strains show an equivalent performance by the end of the trial period. HL rats also perform more efficiently in a double working and reference memory task. On the other hand, Wistar rats show better reference memory performance on the final (8–10) days of training. Wistar rats were less active and more anxious than HL rats. These data suggest that strain-dependent variations in hippocampal synaptic plasticity occur in different hippocampal synapses. A clear correlation with differences in spatial learning is not evident however

Relationship of Hippocampal Theta and Gamma Oscillations to Potentiation of Synaptic Transmission

In the hippocampus in vivo, both synaptic plasticity and network activity are closely interdependent. We have found that immediately after an attempt to induce long-term potentiation (LTP), changes in theta (5–10 Hz) and gamma (30–100 Hz) activity correlate tightly with the occurrence of LTP, suggesting that tetanisation-driven activation of sensory inputs synchronises the activity of granule cells and interneurons, and thus, facilitates the encoding of acquired stimuli. This results in increase of theta and gamma power, and elevates the probability that afferent stimuli both coincide with the peak of theta cycle and reach their post-synaptic target within the gamma time-window (of 10–30 ms). Both these mechanisms can effectively shift the direction, of tetanisation-induced changes in synaptic weight, towards potentiation and induction of LTP. Here, we discuss our findings in the context of possible mechanisms that link theta and gamma oscillations with LTP induction, as well as their role in information processing and formation of memories

Long-Term Plasticity Is Proportional to Theta-Activity

Background: Theta rhythm in the hippocampal formation is a main feature of exploratory behaviour and is believed to enable the encoding of new spatial information and the modification of synaptic weights. Cyclic changes of dentate gyrus excitability during theta rhythm are related to its function, but whether theta epochs per se are able to alter network properties of dentate gyrus for long time-periods is still poorly understood. Methodology/Principal Findings: We used low-frequency stimulation protocols that amplify the power of endogenous theta oscillations, in order to estimate the plasticity effect of endogenous theta oscillations on a population level. We found that stimulation-induced augmentation of the theta rhythm is linked to a subsequent increase of neuronal excitability and decrease of the synaptic response. This EPSP-to-Spike uncoupling is related to an increased postsynaptic spiking on the positive phases of theta frequency oscillations. Parallel increase of the field EPSP slope and the population spike occurs only after concurrent pre- and postsynaptic activation. Furthermore, we observed that long-term potentiation (.24 h) occurs in the dentate gyrus of freely behaving adult rats after phasic activity of entorhinal afferents in the theta-frequency range. This plasticity is proportional to the field bursting activity of granule cells during the stimulation, and may comprise a key step in spatial information transfer. Long-term potentiation of the synaptic component occurs only when the afferent stimulus precedes the evoked population burst, and is input-specific

Distinct Time-Course of Alterations of Groups I and II Metabotropic Glutamate Receptor and GABAergic Receptor Expression Along the Dorsoventral Hippocampal Axis in an Animal Model of Psychosis

Psychosis is a clinical state that encompasses a range of abnormal conditions, including distortions in sensory information processing and the resultant delusional thinking, emotional discordance and cognitive impairments. Upon developing this condition, the rate at which cognitive and behavioral deteriorations progress steadily increases suggesting an active contribution of the first psychotic event to the progression of structural and functional abnormalities and disease establishment in diagnosed patients. Changes in GABAergic and glutamatergic function, or expression, in the hippocampus have been proposed as a key factor in the pathophysiology of psychosis. However, little is known as to the time-point of onset of putative changes, to what extent they are progressive, and their relation to disease stabilization. Here, we characterized the expression and distribution patterns of groups I and II metabotropic glutamate (mGlu) receptors and GABA receptors 1 week and 3 months after systemic treatment with an N-methyl-D-aspartate receptor (NMDAR) antagonist (MK801) that is used to model a psychosis-like state in adult rats. We found an early alteration in the expression of mGlu1, mGlu2/3, and GABAB receptors across the hippocampal dorsoventral and transverse axes. This expanded to include an up-regulation of mGlu5 levels across the entire CA1 region and a reduction in GABAB expression, as well as GAD67-positive interneurons particularly in the dorsal hippocampus that appeared 3 months after treatment. Our findings indicate that a reduction of excitability may occur in the hippocampus soon after first-episode psychosis. This changes, over time, into increased excitability. These hippocampus-specific alterations are likely to contribute to the pathophysiology and stabilization of psychosis

MGluR5 Mediates the Interaction between Late-LTP, Network Activity, and Learning

Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5–10 Hz) and gamma (30–100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning