Rat Hippocampal Area Research Articles

Adenosine A1 receptor antagonist-induced facilitation of postsynaptic AMPA currents in pyramidal neurons of the rat hippocampal CA2 area.

Adenosine A1 receptors (A1R) are widely expressed in hippocampal pyramidal neurons and their presynaptic terminals. It is well known that endogenous adenosine regulates hippocampal function through the activation of A1R in hippocampal pyramidal neurons and has been reported that blockade of A1R induces stronger potentiation of excitatory synaptic transmission in CA2 pyramidal neurons than in CA1 pyramidal neurons. This strong potentiation of CA2 neurons is thought to be caused by the specific modulation of excitatory synaptic transmission through postsynaptic A1R. However, the direct effects of A1R on postsynaptic AMPA channels remain unknown because of the technical difficulties of patch-clamp recording from mature hippocampal CA2 neurons. We recorded synaptic currents from pyramidal neurons in CA1 and CA2 and analyzed the effects of an A1R antagonist on stimulation-evoked synaptic transmission and local application-induced postsynaptic AMPA currents. The antagonist increased the amplitude of evoked synaptic transmission in neurons in both CA1 and CA2. This facilitation was larger in pyramidal neurons in CA2 than in CA1. The antagonist also increased postsynaptic AMPA currents in neurons in CA2 but not in CA1. This facilitation of CA2 AMPA currents was occluded by the intracellular application of a G-protein blocker. Even with the blockade of postsynaptic G-protein signaling, the A1R antagonist increased evoked synaptic transmission in neurons in CA2. These results suggest that synaptic transmission in pyramidal neurons in CA2 is regulated by both presynaptic and postsynaptic A1R. Moreover, A1R regulate excitatory synaptic transmission in pyramidal neurons in CA2 through the characteristic postsynaptic modulation of AMPA currents.

Inhibition of glutamatergic transmission and neuronal excitability by oxycodone in the rat hippocampal CA3 neurons.

Oxycodone, a semisynthetic opioid analgesic with actions similar to morphine, is extensively prescribed for treatment of moderate to severe acute pain. Given that glutamate plays a crucial role in mediating pain transmission, the purpose of this study was to investigate the effect of oxycodone on glutamatergic synaptic transmission in rat hippocampal CA3 area, which is associated with the modulation of nociceptive perception. Whole-cell patch-clamp recordings revealed that oxycodone effectively reduced presynaptic glutamate release, as detected by decreased frequencies of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature EPSCs (mEPSCs), without eliciting significant changes in the amplitudes of sEPSCs and mEPSCs and glutamate-evoked inward currents. The inhibitory effect of oxycodone on the frequency of sEPSCs was blocked by the nonselective opioid receptor antagonist naloxone. In addition, oxycodone suppressed burst firing induced by 4-aminopyridine and tonic repetitive firing evoked by the applied depolarizing current. These results suggest that oxycodone inhibits spontaneous presynaptic glutamate release possibly by activating opioid receptors and consequently suppressing the neuronal excitability of hippocampal CA3 neurons.

Developmental onset of enduring long-term potentiation in mouse hippocampus.

Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L-LTP), lasting >3 hr, occurs abruptly at postnatal day 12 (P12) in the stratum radiatum of rat hippocampal area CA1. The goal here was to determine the developmental profile of synaptic plasticity leading to L-LTP in the mouse hippocampus. Two mouse strains and two mutations known to affect synaptic plasticity were chosen: C57BL/6J and Fmr1-/y on the C57BL/6J background, and 129SVE and Hevin-/- (Sparcl1-/- ) on the 129SVE background. Like rats, hippocampal slices from all of the mice showed test pulse-induced depression early during development that was gradually resolved with maturation by 5 weeks. All the mouse strains showed a gradual progression between P10-P35 in the expression of short-term potentiation (STP), lasting ≤1 hr. In the 129SVE mice, L-LTP onset (>25% of slices) occurred by 3 weeks, reliable L-LTP (>50% slices) was achieved by 4 weeks, and Hevin-/- advanced this profile by 1 week. In the C57BL/6J mice, L-LTP onset occurred significantly later, over 3-4 weeks, and reliability was not achieved until 5 weeks. Although some of the Fmr1-/y mice showed L-LTP before 3 weeks, reliable L-LTP also was not achieved until 5 weeks. L-LTP onset was not advanced in any of the mouse genotypes by multiple bouts of theta-burst stimulation at 90 or 180 min intervals. These findings show important species differences in the onset of STP and L-LTP, which occur at the same age in rats but are sequentially acquired in mice.

Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits.

CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells' whole transcriptome, can determine cell-type identity.

Group III metabotropic glutamate receptors gate long-term potentiation and synaptic tagging/capture in rat hippocampal area CA2.

Metabotropic glutamate receptors (mGluRs) play an important role in synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic glutamate receptors are known to down-regulate cAMP-dependent signaling pathways via the activation of Gi/o proteins. Here, we provide evidence that inhibition of group III mGluRs by specific antagonists permits an NMDA receptor- and protein synthesis-dependent long-lasting synaptic potentiation in the apparently long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. Moreover, long-lasting potentiation of these synapses transforms a transient synaptic potentiation of the entorhinal cortical (EC)-CA2 synapses into a stable long-lasting LTP, in accordance with the synaptic tagging/capture hypothesis (STC). Furthermore, this study also sheds light on the role of ERK/MAPK protein signaling and the downregulation of STEP protein in the group III mGluR inhibition-mediated plasticity in the hippocampal CA2 region, identifying them as critical molecular players. Thus, the regulation of group III mGluRs provides a conducive environment for the SC-CA2 synapses to respond to events that could lead to activity-dependent synaptic plasticity.

Structural plasticity of dendritic secretory compartments during LTP-induced synaptogenesis.

Long-term potentiation (LTP), an increase in synaptic efficacy following high-frequency stimulation, is widely considered a mechanism of learning. LTP involves local remodeling of dendritic spines and synapses. Smooth endoplasmic reticulum (SER) and endosomal compartments could provide local stores of membrane and proteins, bypassing the distant Golgi apparatus. To test this hypothesis, effects of LTP were compared to control stimulation in rat hippocampal area CA1 at postnatal day 15 (P15). By two hours, small spines lacking SER increased after LTP, whereas large spines did not change in frequency, size, or SER content. Total SER volume decreased after LTP consistent with transfer of membrane to the added spines. Shaft SER remained more abundant in spiny than aspiny dendritic regions, apparently supporting the added spines. Recycling endosomes were elevated specifically in small spines after LTP. These findings suggest local secretory trafficking contributes to LTP-induced synaptogenesis and primes the new spines for future plasticity.

Beneficial effects of Spirulina platensis, voluntary exercise and environmental enrichment against adolescent stress induced deficits in cognitive functions, hippocampal BDNF and morphological remolding in adult female rats

Chronic exposure to stress during adolescent period has been demonstrated to impair cognitive functions and the dendritic morphology of pyramidal neurons in the rat hippocampal CA3 area. The present study investigated the combined protective effects of Spirulina platensis (SP), a supplement made from blue-green algae with neuroprotective properties, voluntary exercise (EX) and environmental enrichment (EE) against cognitive deficits, alternations in hippocampal BDNF levels, and abnormal neuronal remodeling in adult female rats (PND 60) induced by exposure to chronic restraint stress during adolescent period (PND 30–40). Rats were exposed to restraint stress (2 h/day for 10 days, PND 30–40). Then, the animals were subjected to treatment with SP (200 mg/kg/day), EX, EE and the combined treatments (SP + EX, and SP + EE) between PND 41 and 55 of age. Following the interventions, spatial learning and memory, passive avoidance performance, hippocampal dendritic morphology and BDNF levels were assessed. Results showed that plasma corticosterone levels increased at PND 40 and remained elevated at PND 55 and 70 in the stressed rats. Stressed rats showed deficits in spatial learning and memory and passive avoidance performance, decreased BDNF levels in the hippocampus, and reduced apical dendritic length and branch points of the CA3 pyramidal neurons. These deficits were alleviated by the SP, EX and EE, and the combined treatments, which accompanied with a decline in serum corticosterone in stressed animals. Some treatments even enhanced cognitive functions, and BDNF levels and neuroanatomical remodeling in the hippocampus of non-stressed animals. Our findings provide important evidences that physical activity, exposure to EE, and the SP treatment during adolescent period can protect against adolescent stress induced behavioral, biochemical and neuroanatomical impairments in adulthood.

Long-term population spike-timing-dependent plasticity promotes synaptic tagging but not cross-tagging in rat hippocampal area CA1

In spike-timing-dependent plasticity (STDP), the direction and degree of synaptic modification are determined by the coherence of pre- and postsynaptic activities within a neuron. However, in the adult rat hippocampus, it remains unclear whether STDP-like mechanisms in a neuronal population induce synaptic potentiation of a long duration. Thus, we asked whether the magnitude and maintenance of synaptic plasticity in a population of CA1 neurons differ as a function of the temporal order and interval between pre- and postsynaptic activities. Modulation of the relative timing of Schaffer collateral fibers (presynaptic component) and CA1 axons (postsynaptic component) stimulations resulted in an asymmetric population STDP (pSTDP). The resulting potentiation in response to 20 pairings at 1 Hz was largest in magnitude and most persistent (4 h) when presynaptic activity coincided with or preceded postsynaptic activity. Interestingly, when postsynaptic activation preceded presynaptic stimulation by 20 ms, an immediate increase in field excitatory postsynaptic potentials was observed, but it eventually transformed into a synaptic depression. Furthermore, pSTDP engaged in selective forms of late-associative activity: It facilitated the maintenance of tetanization-induced early long-term potentiation (LTP) in neighboring synapses but not early long-term depression, reflecting possible mechanistic differences with classical tetanization-induced LTP. The data demonstrate that a pairing of pre- and postsynaptic activities in a neuronal population can greatly reduce the required number of synaptic plasticity-evoking events and induce a potentiation of a degree and duration similar to that with repeated tetanization. Thus, pSTDP determines synaptic efficacy in the hippocampal CA3-CA1 circuit and could bias the CA1 neuronal population toward potentiation in future events.

Intermittent fasting promotes prolonged associative interactions during synaptic tagging/capture by altering the metaplastic properties of the CA1 hippocampal neurons.

Metaplasticity is the inherent property of a neuron or neuronal population to undergo activity-dependent changes in neural function that modulate subsequent synaptic plasticity. Here we studied the effect of intermittent fasting (IF) in governing the interactions of associative plasticity mechanisms in the pyramidal neurons of rat hippocampal area CA1. Late long-term potentiation and its associative mechanisms such as synaptic tagging and capture at an interval of 120 min were evaluated in four groups of animals, AL (Ad libitum), IF12 (daily IF for 12 h), IF16 (daily IF for 16 h) and EOD (every other day IF for 24 h). IF had no visible effect on the early or late plasticity but it manifested a critical role in prolonging the associative interactions between weak and strong synapses at an interval of 120 min in IF16 and EOD animals. However, both IF12 and AL did not show associativity at 120 min. Plasticity genes such as Bdnf and Prkcz, which are well known for their expressions in late plasticity and synaptic tagging and capture, were significantly upregulated in IF16 and EOD in comparison to AL. Specific inhibition of brain derived neurotropic factor (BDNF) prevented the prolonged associativity expressed in EOD. Thus, daily IF for 16 h or more can be considered to enhance the metaplastic properties of synapses by improving their associative interactions that might translate into animprovedmemoryformation.

Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2

The hippocampal area Cornu Ammonis (CA) CA2 is important for social interaction and is innervated by Substance P (SP)-expressing supramammillary (SuM) nucleus neurons. SP exerts neuromodulatory effects on pain processing and central synaptic transmission. Here we provide evidence that SP can induce a slowly developing NMDA receptor- and protein synthesis-dependent potentiation of synaptic transmission that can be induced not only at entorhinal cortical (EC)-CA2 synapses but also at long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. In addition, SP-induced potentiation of SC-CA2 synapses transforms a short-term potentiation of EC-CA2 synaptic transmission into LTP, consistent with the synaptic tagging and capture hypothesis. Interestingly, this SP-induced potentiation and associative interaction between the EC and SC inputs of CA2 neurons is independent of the GABAergic system. In addition, CaMKIV and PKMζ play a critical role in the SP-induced effects on SC-CA2 and EC-CA2 synapses. Thus, afferents from SuM neurons are ideally situated to prime CA2 synapses for the formation of long-lasting plasticity and associativity.

Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area.

Neuronal synchronization at gamma band frequency (20–80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 μM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

Morphofunctional Modifications of Neurocytes of the Rat Hippocampal CA3 Area after Experimental Thermal Trauma

In experiments on mature male Wistar rats, the dynamics of morphological modifications of neurocytes of the hippocampal CA3 area after a severe thermal trauma were examined. The pattern and degree of morphofunctional changes in the nerve cells depended significantly on the time interval after thermal trauma; their intensity correlated with the stages of burn disease. At stages of acute shock and early toxemia (days 1 to 7), mostly effects that could be interpreted as adaptive/compensatory reactions were observed, although initial signs of destructive changes were also obvious. At stages of late toxemia and septicotoxemia (days 14 to 21), deep irreversible destructive modifications in a considerable part of neurocytes of the hippocampal CA3 area became appreciable. The proportions of neurocytes belonging to different morphological types and values of the nucleo-cytoplasmic ratio (NCR) in such cells changed significantly. After an experimental burn, the total density of neurocytes gradually decreased, while portions of sharply hypo- and hyperchromic cells, in which NCRs underwent maximum modifications, increased. Electron microscopy of CA3 nerve cell demonstrated the development of destructive changes in the nuclei and cytoplasmic structures (degranulation of the endoplasmic reticulum, decrease in the number of ribosomes and polysomes, hypertrophy of the mitochondria with clarification of their matrix and destruction of mitochondrial cristae, and increase in the number of lysosomes). Therefore, severe thermal trauma induces significant morphofunctional modifications of neurocytes in the hippocampal CA3 area.

The PI3K-AKT-mTOR pathway activates recovery from general anesthesia.

We investigated roles of PI3K-AKT-mTOR pathway in recovery from general anesthesia. Sprague-Dawley rats divided into five groups: saline+artificial cerebrospinal fluid (ACSF; Group A), ketamine+ACSF (Group B), ketamine+IGF-1 (Group C), ketamine+PI3K inhibitor (Group D), and PI3K/Akt agonists (Group E). Proportion of δ waves on ECoGs was recorded. Rats were tested for duration of loss of righting reflex (LORR), ataxic period and behavior in Morris water maze. mRNA and protein expression of members of PI3K-AKT-mTOR pathway were measured by RT-qPCR and Western blots. Histopathologic changes in hippocampal tissues observed by HE staining. We found that the proportion of δ waves decreased in Group C, while increased in Group D compared with Group B; the durations of LORR and ataxic period were shorter in Group C, but longer in Group D. In Morris water maze, escape latency (EL) and duration and frequency of staying on platform was shorter in Group C and longer in Group D than in Group B. Group A exhibited low expression of proteins in PI3K-AKT-mTOR pathway, while p-AKT, p-mTOR and p-P70S6K expression increased in cerebral cortex, brain stem, and thalamus in Group C. By contrast, expression of those proteins was lower in Group D than Group B. Those proteins expressions were higher in Group E than in Group A. HE staining showed that anesthesia may induce cell apoptosis in rat hippocampal CA1 areas, and PI3K/Akt agonists could inhibit apoptosis. Our results suggest that activation of PI3K-AKT-mTOR pathway may promote recovery from general anesthesia and enhance spatial learning and memory.

Pilocarpine-induced epilepsy alters the expression and daily variation of the nuclear receptor RORα in the hippocampus of rats.

It is widely known that there is an increase in the inflammatory responses and oxidative stress in temporal lobe epilepsy (TLE). Further, the seizures follow a circadian rhythmicity. Retinoic acid receptor-related orphan receptor alpha (RORα) is related to anti-inflammatory and antioxidant enzyme expression and is part of the machinery of the biological clock and circadian rhythms. However, the participation of RORα in this neurological disorder has not been studied. The aim of this study was to evaluate the RORα mRNA and protein content profiles in the hippocampus of rats submitted to a pilocarpine-induced epilepsy model at different time points throughout the 24-h light-dark cycle analyzing the influence of the circadian rhythm in the expression pattern during the acute, silent, and chronic phases of the experimental model. Real-time PCR and immunohistochemistry results showed that RORα mRNA and protein expressions were globally reduced in both acute and silent phases of the pilocarpine model. However, 60days after the pilocarpine-induced status epilepticus (chronic phase), the mRNA expression was similar to the control except for the time point 3h after the lights were turned off, and no differences were found in immunohistochemistry. Our results indicate that the status epilepticus induced by pilocarpine is able to change the expression and daily variation of RORα in the rat hippocampal area during the acute and silent phases. These findings enhance our understanding of the circadian pattern present in seizures as well as facilitate strategies for the treatment of seizures.

Early adenosine release contributes to hypoxia-induced disruption of stimulus-induced sharp wave-ripple complexes in rat hippocampal area CA3.

We investigated the effects of hypoxia on sharp wave-ripple complex (SPW-R) activity and recurrent epileptiform discharges in rat hippocampal slices, and the mechanisms underlying block of this activity. Oxygen levels were measured using Clark-style oxygen sensor microelectrodes. In contrast to recurrent epileptiform discharges, oxygen consumption was negligible during SPW-R activity. These network activities were reversibly blocked when oxygen levels were reduced to 20% or less for 3min. The prolongation of hypoxic periods to 6min caused reversible block of SPW-Rs during 20% oxygen and irreversible block when 0% oxygen (anoxia) was applied. In contrast, recurrent epileptiform discharges were more resistant to prolonged anoxia and almost fully recovered after 6min of anoxia. SPW-Rs were unaffected by the application of 1-butyl-3-(4-methylphenylsulfonyl) urea, a blocker of KATP channels, but they were blocked by activation of adenosine A1 receptors. In support of a modulatory function of adenosine, the amplitude and incidence of SPW-Rs were increased during application of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Interestingly, hypoxia decreased the frequency of miniature excitatory post-synaptic currents in CA3 pyramidal cells, an effect that was converted into increased frequency by the adenosine A1 agonist DPCPX. In addition, DPCPX also delayed the onset of hypoxia-mediated block of SPW-Rs. Our data suggest that early adenosine release during hypoxia induces a decrease in pre-synaptic glutamate release and that both might contribute to transient block of SPW-Rs during hypoxia/anoxia in area CA3.

Induction of long-term oscillations in the γ frequency band by nAChR activation in rat hippocampal CA3 area

The hippocampal neuronal network oscillation at γ frequency band (γ oscillation) is generated by the precise interaction between interneurons and principle cells. γ oscillation is associated with attention, learning and memory and is impaired in the diseased conditions such as Alzheimer’s disease (AD) and schizophrenia. Nicotinic acetylcholine receptor (nAChR) plays an important role in the regulation of hippocampal neurotransmission and network activity. It is not known whether nicotine modulates plasticity of network activity at γ oscillations in the hippocampus. In this study we investigated the effects of nicotine on the long-term changes of KA-induced γ oscillations. We found that hippocampal γ oscillations can be enhanced by a low concentration of nicotine (1μM), such an enhancement lasts for hours after washing out of nicotine, suggesting a form of synaptic plasticity, named as long-term oscillation at γ frequency band (LTOγ). Nicotine-induced LTOγ was mimicked by the selective α4β2 but not by α7 nAChR agonist and was involved in N-methyl-d-aspartate (NMDA) receptor activation as well as depended on excitatory and inhibitory neurotransmission. Our results indicate that nAChR activation induced plasticity in γ oscillation, which may be beneficial for the improvement of cognitive deficiency in AD and schizophrenia.

The modulation of nicotinic acetylcholine receptors on the neuronal network oscillations in rat hippocampal CA3 area.

γ oscillations are associated with higher brain functions such as memory, perception and consciousness. Disruption of γ oscillations occur in various neuro-psychological disorders such as schizophrenia. Nicotinic acetylcholine receptors (nAChR) are highly expressed in the hippocampus, however, little is known about the role on hippocampal persistent γ oscillation. This study examined the effects of nicotine and selective nAChR agonists and antagonists on kainate-induced persistent γ oscillation in rat hippocampal slices. Nicotine enhanced γ oscillation at concentrations of 0.1–10 μM, but reduced it at a higher concentration of 100 μM. The enhancement on γ oscillation can be best mimicked by co-application of α4β2- and α7- nAChR agonist and reduced by a combination of nAChR antagonists, DhβE and MLA. However, these nAChR antagonists failed to block the suppressing role of nicotine on γ. Furthermore, we found that the NMDA receptor antagonist D-AP5 completely blocked the effect of nicotine. These results demonstrate that nicotine modulates γ oscillations via α7 and α4β2 nAChR as well as NMDA activation, suggesting that nAChR activation may have a therapeutic role for the clinical disorder such as schizophrenia, which is known to have impaired γ oscillation and hypo-NMDA receptor function.

Pannexin-1-mediated ATP release from area CA3 drives mGlu5-dependent neuronal oscillations

The activation of Group I metabotropic glutamate receptors (GI mGluRs) in the hippocampus results in the appearance of persistent bursts of synchronised neuronal activity. In response to other stimuli, such activity is known to cause the release of the purines ATP and its neuroactive metabolite, adenosine. We have thus investigated the potential release and role of the purines during GI mGluR-induced oscillations in rat hippocampal areas CA3 and CA1 using pharmacological techniques and microelectrode biosensors for ATP and adenosine. The GI mGluR agonist DHPG induced both persistent oscillations in neuronal activity and the release of adenosine in areas CA1 and CA3. In contrast, the DHPG-induced release of ATP was only observed in area CA3. Whilst adenosine acting at adenosine A1 receptors suppressed DHPG-induced burst activity, the activation of mGlu5 and P2Y1 ATP receptors were necessary for the induction of DHPG-induced oscillations. Selective inhibition of pannexin-1 hemichannels with a low concentration of carbenoxolone (10 μM) or probenecid (1 mM) did not affect adenosine release in area CA3, but prevented both ATP release in area CA3 and DHPG-induced bursting. These data reveal key aspects of GI mGluR-dependent neuronal activity that are subject to bidirectional regulation by ATP and adenosine in the initiation and pacing of burst firing, respectively, and which have implications for the role of GI mGluRs in seizure activity and neurodevelopmental disorders.

Within-session dynamics of theta-gamma coupling and high-frequency oscillations during spatial alternation in rat hippocampal area CA1.

Theta-gamma coupling in the hippocampus is thought to be involved in cognitive processes. A large body of research establishes that the hippocampus plays a crucial role in the organization and maintenance of episodic memory, and that sharp-wave ripples (SWR) contribute to memory consolidation processes. Here, we investigated how the local field potentials in the hippocampal CA1 area adapted along with rats' behavioral changes within a session during a spatial alternation task that included a 1-s fixation and a 1.5-s delay. We observed that, as the session progressed, the duration from fixation onset to nose-poking in the choice hole reduced as well as the number of premature responses during the delay. Parallel with the behavioral transitions, the power of high gamma during the delay period increased whereas that of low gamma decreased later in the session. Furthermore, the strength of theta-gamma modulation later in the session showed significant increase as compared to earlier in the session. Examining SWR during the reward period, we found that the number of SWR events decreased as well as the power in a wide frequency range during SWR events. In addition, the correlation between SWR and gamma oscillations just before SWR events was higher in the earlier trials than in the later trials. Our findings support the notion that the inputs from CA3 and entorhinal cortex play a critical role in memory consolidation as well as in cognitive processes. We suggest that SWR and the inputs from the two areas serve to stabilize the task behavior and neural activities.

Theta phase shift in spike timing and modulation of gamma oscillation: a dynamic code for spatial alternation during fixation in rat hippocampal area CA1

Although hippocampus is thought to perform various memory-related functions, little is known about the underlying dynamics of neural activity during a preparatory stage before a spatial choice. Here we focus on neural activity that reflects a memory-based code for spatial alternation, independent of current sensory and motor parameters. We recorded multiple single units and local field potentials in the stratum pyramidale of dorsal hippocampal area CA1 while rats performed a delayed spatial-alternation task. This task includes a 1-s fixation in a nose-poke port between selecting alternating reward sites and so provides time-locked enter-and-leave events. At the single-unit level, we concentrated on neurons that were specifically active during the 1-s fixation period, when the rat was ready and waiting for a cue to pursue the task. These neurons showed selective activity as a function of the alternation sequence. We observed a marked shift in the phase timing of the neuronal spikes relative to the theta oscillation, from the theta peak at the beginning of fixation to the theta trough at the end of fixation. The gamma-band local field potential also changed during the fixation period: the high-gamma power (60-90 Hz) decreased and the low-gamma power (30-45 Hz) increased toward the end. These two gamma components were observed at different phases of the ongoing theta oscillation. Taken together, our data suggest a switch in the type of information processing through the fixation period, from externally cued to internally generated.