Muscarinic Modulation of Synaptic Transmission and Short-Term Plasticity in the Dorsal and Ventral Hippocampus.

Muscarinic neurotransmission is fundamentally involved in supporting several brain functions by modulating flow of information in brain neural circuits including the hippocampus which displays a remarkable functional segregation along its longitudinal axis. However, how muscarinic neuromodulation contributes to the functional segregation along the hippocampus remains unclear. In this study we show that the nonselective muscarinic receptor agonist carbachol similarly suppresses basal synaptic transmission in the dorsal and ventral CA1 hippocampal field, in a concentration-depended manner. Furthermore, using a ten-pulse stimulation train of varying frequency we found that carbachol changes the frequency filtering properties more in ventral than dorsal hippocampus by facilitating synaptic inputs at a wide range of input frequencies in the ventral compared with dorsal hippocampus. Using the M2 receptor antagonist gallamine and the M4 receptor antagonist tropicamide, we found that M2 receptors are involved in controlling basal synaptic transmission and short-term synaptic plasticity (STSP) in the ventral but not the dorsal hippocampus, while M4 receptors participate in modulating basal synaptic transmission and STSP in both segments of the hippocampus. These results were corroborated by the higher protein expression levels of M2 receptors in the ventral compared with dorsal hippocampus. We conclude that muscarinic transmission modulates excitatory synaptic transmission and short-term synaptic plasticity along the entire rat hippocampus by acting through M4 receptors and recruiting M2 receptors only in the ventral hippocampus. Furthermore, M4 receptors appear to exert a permissive role on the actions of M2 receptors on STSP in the ventral hippocampus. This dorsoventral differentiation of muscarinic modulation is expected to have important implications in information processing along the endogenous hippocampal circuitry.

Multi-level profiling of the Fmr1 KO rat unveils altered behavioral traits along with aberrant glutamatergic function.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and the most prevalent monogenic cause of autism. Although the knockout (KO) of the Fmr1 gene homolog in mice is primarily used for elucidating the neurobiological substrate of FXS, there is limited association of the experimental data with the pathophysiological condition in humans. The use of Fmr1 KO rats offers additional translational validity in this regard. Therefore, we employed a multi-level approach to study the behavioral profile and the glutamatergic and GABAergic neurotransmission status in pathophysiology-associated brain structures of Fmr1 KO rats, including the recordings of evoked and spontaneous field potentials from hippocampal slices, paralleled with next-generation RNA sequencing (RNA-seq). We found that these rats exhibit hyperactivity and cognitive deficits, along with characteristic bidirectional glutamatergic and GABAergic alterations in the prefrontal cortex and the hippocampus. These results are coupled to affected excitability and local inhibitory processes in the hippocampus, along with a specific transcriptional profile, highlighting dysregulated hippocampal network activity in KO rats. Overall, our data provide novel insights concerning the biobehavioral profile of FmR1 KO rats and translationally upscales our understanding on pathophysiology and symptomatology of FXS syndrome.

Septotemporal variation of information processing in the hippocampus of Fmr1 KO rat.

Introduction Fragile X messenger ribonucleoprotein (FMRP) is a protein involved in many neuronal processes in the nervous system including the modulation of synaptic transmission. Loss of FMRP produces the fragile X syndrome (FXS), a neurodevelopmental disorder affecting synaptic and neuronal function and producing cognitive impairments. However, the effects of FXS on short-term processing of synaptic inputs and neuronal outputs in the hippocampus have not yet been sufficiently clarified. Furthermore, it is not known whether dorsal and ventral hippocampus are affected similarly or not in FXS. Method We used a Fmr1 knock-out (KO) rat model of FXS and recordings of evoked field potentials from the CA1 field of transverse slices from both the dorsal and the ventral hippocampus of adult rats. Results Following application of a frequency stimulation protocol consisting of a ten-pulse train and recordings of fEPSP, we found that the dorsal but not ventral KO hippocampus shows altered short-term synaptic plasticity. Furthermore, applying the frequency stimulation protocol and recordings of population spikes, both segments of the KO hippocampus display altered short-term neuronal dynamics. Conclusions These data suggest that short-term processing of synaptic inputs is affected in the dorsal, not ventral FXS hippocampus, while short-term processing of neuronal output is affected in both segments of the FXS hippocampus in a similar way. These FXS-associated changes may have significant impact on the functions of the dorsal and ventral hippocampus in individuals with FXS.

α7 nicotinic acetylcholine receptors induce long-term synaptic enhancement in the dorsal but not ventral hippocampus.

Agents that positively modulate the activity of α7nAChRs are used as cognitive enhancers and for the treatment of hippocampus-dependent functional decline. However, it is not known whether the expression and the effects of α7nAChRs apply to the entire longitudinal axis of the hippocampus equally. Given that cholinergic system-involving hippocampal functions are not equally distributed along the hippocampus, we comparatively examined the expression and the effects of α7nAChRs on excitatory synaptic transmission between the dorsal and the ventral hippocampal slices from adult rats. We found that α7nAChRs are equally expressed in the CA1 field of the two segments of the hippocampus. However, activation of α7nAChRs by their highly selective agonist PNU 282987 induced a gradually developing increase in field excitatory postsynaptic potential only in the dorsal hippocampus. This long-term potentiation was not reversed upon application of nonselective nicotinic receptor antagonist mecamylamine, but the induction of potentiation was prevented by prior blockade of α7nAChRs by their antagonist MG 624. In contrast to the long-term synaptic plasticity, we found that α7nAChRs did not modulate short-term synaptic plasticity in either the dorsal or the ventral hippocampus. These results may have implications for the role that α7nAChRs play in specifically modulating functions that depend on the normal function of the dorsal hippocampus. We propose that hippocampal functions that rely on a direct α7 nAChR-mediated persistent enhancement of glutamatergic synaptic transmission are preferably supported by dorsal but not ventral hippocampal synapses.

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene (Fmr1) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABAA receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1-KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability.

Increased Inhibition May Contribute to Maintaining Normal Network Function in the Ventral Hippocampus of a Fmr1-Targeted Transgenic Rat Model of Fragile X Syndrome.

A common neurobiological mechanism in several neurodevelopmental disorders, including fragile X syndrome (FXS), is alterations in the balance between excitation and inhibition in the brain. It is thought that in the hippocampus, as in other brain regions, FXS is associated with increased excitability and reduced inhibition. However, it is still not known whether these changes apply to both the dorsal and ventral hippocampus, which appear to be differently involved in neurodegenerative disorders. Using a Fmr1 knock-out (KO) rat model of FXS, we found increased neuronal excitability in both the dorsal and ventral KO hippocampus and increased excitatory synaptic transmission in the dorsal hippocampus. Interestingly, synaptic inhibition is significantly increased in the ventral but not the dorsal KO hippocampus. Furthermore, the ventral KO hippocampus displays increased expression of the α1GABAA receptor subtype and a remarkably reduced rate of epileptiform discharges induced by magnesium-free medium. In contrast, the dorsal KO hippocampus displays an increased rate of epileptiform discharges and similar expression of α1GABAA receptors compared with the dorsal WT hippocampus. Blockade of α5GABAA receptors by L-655,708 did not affect epileptiform discharges in any genotype or hippocampal segment, and the expression of α5GABAA receptors did not differ between WT and KO hippocampus. These results suggest that the increased excitability of the dorsal KO hippocampus contributes to its heightened tendency to epileptiform discharges, while the increased phasic inhibition in the Fmr1-KO ventral hippocampus may represent a homeostatic mechanism that compensates for the increased excitability reducing its vulnerability to epileptic activity.

Septotemporal variation in modulation of synaptic transmission, paired-pulse ratio and frequency facilitation/depression by adenosine and GABAB receptors in the rat hippocampus.

Short-term synaptic plasticity represents a fundamental mechanism in neural information processing and is regulated by neuromodulators. Here, using field recordings from the CA1 region of adult rat hippocampal slices, we show that excitatory synaptic transmission is suppressed by strong but not moderate activation of adenosine A1 receptors by 2-Chloro-N6-cyclopentyladenosine (CCPA) more in the dorsal than the ventral hippocampus; in contrast, both mild and strong activation of GABAB receptors by baclofen (1 µM, 10 µM) suppress synaptic transmission more in the ventral than the dorsal hippocampus. Using a 10-pulse stimulation train of variable frequency, we found that CCPA modulates short-term synaptic plasticity independently of the suppression of synaptic transmission in both segments of the hippocampus and at stimulation frequencies greater than 10 Hz. However, specifically regarding the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D) we found significant drug action before but not after adjusting conditioning responses to control levels. Activation of GABABRs by baclofen suppressed synaptic transmission more in the ventral than the dorsal hippocampus. Furthermore, relatively high (10 µM) but not low (1 µM) baclofen concentration enhanced both PPR and FF in both hippocampal segments at stimulation frequencies greater than 1 Hz, independently of the suppression of synaptic transmission by baclofen. These results show that A1Rs and GABABRs control synaptic transmission more effectively in the dorsal and the ventral hippocampus, respectively, and suggest that these receptors modulate PPR and FF/D at different frequency bands of afferent input, in both segments of the hippocampus.

Age-dependent modulation of short-term neuronal dynamics in the dorsal and ventral rat hippocampus.

Brain aging is associated with alterations in the behavioral capacity to process information, due to mechanisms that are still largely unclear. Short-term neuronal activity dynamics are basic properties of local brain networks profoundly involved in neural information processing. In this study, we investigated the properties of short-term changes in excitatory synaptic transmission and neuronal excitation in the CA1 field of dorsal and ventral hippocampal slices from young adult and old rats. We found that short-term synaptic plasticity (i.e. short-term dynamics of input to CA1 circuit) does not significantly differ between young and old dorsal or ventral hippocampus. However, short-term dynamics of hippocampal output differ markedly between young and old rats. Notably, age-dependent alterations in short-term neuronal dynamics were detected mainly in the dorsal hippocampus. Thus, the dorsal hippocampus of young rats can detect and facilitate transmission of 1-30 Hz input and depress transmission of higher-frequency input. In contrast, the old dorsal hippocampus appears unable to transmit information in a frequency-dependent discriminatory manner. Furthermore, the amplification of steady-state output at frequencies < 40 Hz is considerably lower in the old than the young dorsal hippocampus. The old ventral hippocampus did not show major alterations in short-term processing of neural information, though under conditions of intense afferent activation, neuronal output of the ventral hippocampus is depressed at steady-state more in old than in young rats. These results suggest that aging is accompanied by alterations in neural information processing mainly in the dorsal hippocampus, which displays a narrower dynamic range of frequency-dependent transient changes in neuronal activity in old compared with young adult rats. These alterations in short-term dynamics may relate to deficits in processing ongoing activity seen in old individuals.

Septotemporal variation in beta-adrenergic modulation of short-term dynamics in the hippocampus.

Recent evidence shows a greater facilitating effect of beta-adrenergic receptors (ß-ARs) on long-term synaptic plasticity in the ventral versus the dorsal hippocampus. Here, using field potentials from the CA1 area and a ten-pulse stimulation train of varying frequency we show that activation of ß-ARs by isoproterenol preferentially facilitates the output from the dorsal hippocampus at the frequency range of 3-40 Hz without affecting short-term synaptic plasticity. Furthermore, isoproterenol increases basal synaptic transmission in the dorsal hippocampus only and enhances basal neuronal excitation more in the dorsal than the ventral hippocampus. These results suggest that ß-AR-modulation of short-term neuronal dynamics differs along the longitudinal axis of the hippocampus, thereby contributing to functional specialization along the same axis.

Frequency-dependent layer-specific differences in short-term synaptic plasticity in the dorsal and ventral CA1 hippocampal field.

Information from the entorhinal cortex arrives to the hippocampal CA1 microcircuit directly through the temporoammonic path (TA) that terminates in the stratum lacunosum-moleculare (SLM), and indirectly through Schaffer collateral pathway (SC) that terminates in the stratum radiatum (SR). By virtue of this input convergence, CA1 circuitry may act to compare and integrate incoming cortical information. Although a remarkable dorsal-ventral difference in short-term plasticity (STP) has been recently described at SC-CA1 synapses, the corresponding properties at TA-CA1 synapses have not been examined. Here, we report that stimulation of TA in the dorsal hippocampus produces significant facilitation of all conditioned responses evoked by 1-30 Hz, peaking at 20-30 Hz, and significant depression of steady-state responses to 50-100 Hz. Dorsal SC-CA1 synapses display a similar pattern of responses, yet, facilitation peaked at 10 Hz and depression (at 75-100 Hz) is weaker. Strikingly, stimulation of TA in the ventral hippocampus produces facilitation of steady-state responses to 1-30 Hz and highly contrasts with the depression of SC-CA1 synapses. Steady-state responses to 40-100 Hz in the ventral hippocampus depress in both layers similarly. High-frequency TA input (40-100 Hz) to the dorsal hippocampus depresses more in proximal than in distal SLM, while low-frequency (1-3 Hz) TA input to the ventral hippocampus facilitates more in distal than in proximal SLM. The present evidence suggests that direct and indirect entorhinal cortical inputs across the septotemporal extent of hippocampal CA1 field display frequency selectivity both in the radial and transverse axes, and that a rapid information processing may take place through direct ventral hippocampal CA1-EC circuit interactions independently of trisynaptic circuit.

Scaling of Network Excitability and Inhibition may Contribute to the Septotemporal Differentiation of Sharp Waves-Ripples in Rat Hippocampus In Vitro.

The functional organization of the hippocampus along its longitudinal (septotemporal or dorsoventral) axis is conspicuously heterogeneous. This functional diversification includes the activity of sharp wave and ripples (SPW-Rs), a complex intrinsic network pattern involved in memory consolidation. In this study, using transverse slices from the ventral and the dorsal rat hippocampus and recordings of CA1 field potentials we studied the development of SPW-Rs and possible changes in local network excitability and inhibition, during in vitro maintenance of the hippocampal tissue. We found that SPW-Rs develop gradually in terms of magnitude and rate of occurrence in the ventral hippocampus. On the contrary, neither the magnitude nor the rate of occurrence significantly changed in dorsal hippocampal slices during their in vitro maintenance. The development of SPW-Rs was accompanied by an increase in local network excitability more in the ventral than in the dorsal hippocampus, and an increase in local network inhibition in the ventral hippocampus only. Furthermore, the amplitude of SPWs positively correlated with the level of maximum excitation of the local neuronal network in both segments of the hippocampus, and the local network excitability and inhibition in the ventral but not the dorsal hippocampus. Blockade of α5 subunit-containing GABAA receptor by L-655,708 significantly reduced the rate of occurrence of SPWs and enhanced the probability of their generation in the form of clusters in the ventral hippocampus without affecting activity in the dorsal hippocampus. The present evidence suggests that a dynamic upregulation of excitation and inhibition in the local neuronal network may significantly contribute to the generation of SPW-Rs, particularly in the ventral hippocampus.

Dorsal-Ventral Differences in Modulation of Synaptic Transmission in the Hippocampus.

Functional diversification along the longitudinal axis of the hippocampus is a rapidly growing concept. Modulation of synaptic transmission by neurotransmitter receptors may importantly contribute to specialization of local intrinsic network function along the hippocampus. In the present study, using transverse slices from the dorsal and the ventral hippocampus of adult rats and recordings of evoked field postsynaptic excitatory potentials (fEPSPs) from the CA1 stratum radiatum, we aimed to compare modulation of synaptic transmission between the dorsal and the ventral hippocampus. We found that transient heterosynaptic depression (tHSD, <2 s), a physiologically relevant phenomenon of regulation of excitatory synaptic transmission induced by paired stimulation of two independent inputs to stratum radiatum of CA1 field, has an increased magnitude and duration in the ventral hippocampus, presumably contributing to increased input segregation in this segment of the hippocampus. GABAB receptors, GABAA receptors, adenosine A1 receptors and L-type voltage-gated calcium channels appear to contribute differently to tHSD in the two hippocampal segments; GABABRs play a predominant role in the ventral hippocampus while both GABABRs and A1Rs play important roles in the dorsal hippocampus. Activation of GABAB receptors by an exogenous agonist, baclofen, robustly and reversibly modulated both the initial fast and the late slow components of excitatory synaptic transmission, expressed by the fEPSPslope and fEPSP decay time constant (fEPSPτ), respectively. Specifically, baclofen suppressed fEPSP slope more in the ventral than in the dorsal hippocampus and enhanced fEPSPτ more in the dorsal than in the ventral hippocampus. Also, baclofen enhanced paired-pulse facilitation in the two hippocampal segments similarly. Blockade of GABAB receptors did not affect basal paired-pulse facilitation in either hippocampal segment. We propose that the revealed dorsal-ventral differences in modulation of synaptic transmission may provide a means for specialization of information processing in the local neuronal circuits, thereby significantly contributing to diversifying neuronal network functioning along the dorsal-ventral axis of hippocampus.

Ih, GIRK, and KCNQ/Kv7 channels differently modulate sharp wave - ripples in the dorsal and ventral hippocampus.

Sharp waves and ripples (SPW-Rs) are endogenous transient patterns of hippocampus local network activity implicated in several functions including memory consolidation, and they are diversified between the dorsal and the ventral hippocampus. Ion channels in the neuronal membrane play important roles in cell and local network function. In this study, using transverse slices and field potential recordings from the CA1 field of rat hippocampus we show that GIRK and KCNQ2/3 potassium channels play a higher role in modulating SPW-Rs in the dorsal hippocampus, while Ih and other KCNQ (presumably KCNQ5) channels, contribute to shaping SPW-R activity more in the ventral than in dorsal hippocampus. Specifically, blockade of Ih channels by ZD 7288 reduced the rate of occurrence of SPW-Rs and increased the generation of SPW-Rs in the form of clusters in both hippocampal segments, while enhanced the amplitude of SPW-Rs only in the ventral hippocampus. Most effects of ZD 7288 appeared to be independent of NMDA receptors' activity. However, the effects of blockade of NMDA receptors depended on the functional state of Ih channels in both hippocampal segments. Blockade of GIRK channels by Tertiapin-Q increased the rate of occurrence of SPW-Rs only in the dorsal hippocampus and the probability of clusters in both segments of the hippocampus. Blockade of KCNQ2/3 channels by XE 991 increased the rate of occurrence of SPW-Rs and the probability of clusters in the dorsal hippocampus, and only reduced the clustered generation of SPW-Rs in the ventral hippocampus. The blocker of KCNQ1/2 channels, that also enhances KCNQ5 channels, UCL 2077, increased the probability of clusters and the power of the ripple oscillation in the ventral hippocampus only. These results suggest that GIRK, KCNQ and Ih channels represent a key mechanism for modulation of SPW-R activity which act differently in the dorsal and ventral hippocampus, fundamentally supporting functional diversification along the dorsal-ventral axis of the hippocampus.

Short-term dynamics of input and output of CA1 network greatly differ between the dorsal and ventral rat hippocampus.

BACKGROUND: The functional heterogeneity of the hippocampus along its longitudinal axis at the level of behavior is an established concept; however, the neurobiological mechanisms are still unknown. Diversifications in the functioning of intrinsic hippocampal circuitry including short-term dynamics of synaptic inputs and neuronal output, that are important determinants of information processing in the brain, may profoundly contribute to functional specializations along the hippocampus. The objectives of the present study were the examination of the role of the GABAA receptor-mediated inhibition, the µ-opioid receptors and the effect of stimulation intensity on the dynamics of both synaptic input and neuronal output of CA1 region in the dorsal and ventral hippocampus. We used recordings of field potentials from adult rat hippocampal slices evoked by brief repetitive activation of Schaffer collaterals. RESULTS: We find that the local CA1 circuit of the dorsal hippocampus presents a remarkably increased dynamic range of frequency-dependent short-term changes in both input and output, ranging from strong facilitation to intense depression at low and high stimulation frequencies respectively. Furthermore, the input-output relationship in the dorsal CA1 circuit is profoundly influenced by frequency and time of presynaptic activation. Strikingly, the ventral hippocampus responds mostly with depression, displaying a rather monotonous input-output relationship over frequency and time. Partial blockade of GABAA receptor-mediated transmission (by 5 µM picrotoxin) profoundly influences input and output dynamics in the dorsal hippocampus but affected only the neuronal output in the ventral hippocampus. M-opioid receptors control short-term dynamics of input and output in the dorsal hippocampus but they play no role in the ventral hippocampus. CONCLUSION: The results demonstrate that information processing by CA1 local network is highly diversified between the dorsal and ventral hippocampus. Transient detection of incoming patterns of activity and frequency-dependent sustained signaling of amplified neuronal information may be assigned to the ventral and dorsal hippocampal circuitry respectively. This disparity should have profound implications for the functional roles ascribed to distinct segments along the long axis of the hippocampus.

Traits of criticality in membrane potential fluctuations of pyramidal neurons in the CA1 region of rat hippocampus.

Evidence that neural circuits are operating near criticality has been provided at various levels of brain organisation with a presumed role in maximising information processing and multiscale activity association. Criticality has been linked to excitation at both the single-cell and network levels, as action potential generation marks an obvious phase transition from a resting to an excitable state. Using in vitro intracellular recordings, we examine irregular, small amplitude membrane potential fluctuations from CA1 pyramidal neurons of Wistar male rats. We show that these fluctuations, confounded with noise, carry information relevant to the neuronal state. The underlying dynamics exhibit intermittent characteristics shown to describe the temporal fluctuations of the order parameter of a macroscopic system at its critical point even in the absence of firing. An externally applied stimulus serves as the control parameter, driving the system in and out of its critical state. Based on our experimental observations we calculate the equivalent of the isothermal critical exponent δh finding a value which depends on the applied stimulus. For each neuron there is a stimulus amplitude for which the critical behaviour becomes most pronounced. The corresponding mean value of δh in the considered ensemble of neurons is δh  ≈ 1.89, close to theoretical predictions for critical networks. Finally, we show that the firing rate of a neuron decreases exponentially with δh .

ß-adrenergic receptors reduce the threshold for induction and stabilization of LTP and enhance its magnitude via multiple mechanisms in the ventral but not the dorsal hippocampus.

The hippocampus is a functionally heterogeneous structure with the cognitive and emotional signal processing ascribed to the dorsal (DH) and the ventral hippocampus (VH) respectively. However, the underlying mechanisms are poorly understood. Noradrenaline is released in hippocampus during emotional arousal modulating synaptic plasticity and memory consolidation through activation of ß adrenergic receptors (ß-ARs). Using recordings of field excitatory postsynaptic potentials from the CA1 field of adult rat hippocampal slices we demonstrate that long-term potentiation (LTP) induced either by theta-burst stimulation (TBS) that mimics a physiological firing pattern of hippocampal neurons or by high-frequency stimulation is remarkably more sensitive to ß-AR activation in VH than in DH. Thus, pairing of subthreshold primed burst stimulation with activation of ß-ARs by their agonist isoproterenol (1 µM) resulted in a reliable induction of NMDA receptor-dependent LTP in the VH without affecting LTP in the DH. Activation of ß-ARs by isoproterenol during application of intense TBS increased the magnitude of LTP in both hippocampal segments but facilitated voltage-gated calcium channel-dependent LTP in VH only. Endogenous ß-AR activation contributed to the stabilization and the magnitude of LTP in VH but not DH as demonstrated by the effects of the ß-ARs antagonist propranolol (10 µM). Exogenous (but not endogenous) ß-AR activation strongly increased TBS-induced facilitation of postsynaptic excitability in VH. In DH, isoproterenol only produced a moderate and GABAergic inhibition-dependent enhancement in the facilitation of synaptic burst responses. Paired-pulse facilitation did not change with LTP at any experimental condition suggesting that expression of LTP does not involve presynaptic mechanisms. These findings suggest that ß-AR may act as a switch that selectively promotes synaptic plasticity in VH through multiple ways and provide thus a first clue to mechanisms that underlie VH involvement in emotionality.

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses.

Hippocampus is importantly involved in dopamine-dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta-burst stimulation-induced long-term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral-CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 µM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50-150 µM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 µM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor-mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.

Electrophysiological evidence for long-axis intrinsic diversification of the hippocampus.

The elongated structure of the hippocampus is critically involved in brain functions of profound importance. The segregation of functions along the longitudinal (septotemporal or dorsoventral) axis of the hippocampus is a slowly developed concept and currently is a widely accepted idea. The segregation of neuroanatomical connections along the hippocampal long axis can provide a basis for the interpretation of the functional segregation. However, an emerging and growing body of data strongly suggests the existence of endogenous diversification in the properties of the local neural network along the long axis of the hippocampus. In particular, recent electrophysiological research provides compelling evidence demonstrating constitutively increased network excitability in the ventral hippocampus with important implications for the endogenous initiation and propagation of physiological hippocampal oscillations yet, under favorable conditions it can also drive the local network towards hyperexcitability. In addition, important specializations in the properties of dorsal and ventral hippocampal synapses may support an optimal signal processing that contributes to the effective execution of the distinct functional roles played by the two hippocampal segments.

Adenosine A2A receptors are required for glutamate mGluR5- and dopamine D1 receptor-evoked ERK1/2 phosphorylation in rat hippocampus: involvement of NMDA receptor.

Interaction between mGluR5 and NMDA receptors (NMDAR) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A2A receptors (A2A R) (J Neurochem, 135, 2015, 714). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show that mGluR5 stimulation or mGluR5/NMDARs co-stimulation synergistically activate ERK1/2 signaling leading to c-Fos expression. Interestingly, both reactions are under the permissive control of endogenous adenosine acting through A2A Rs. Moreover, mGluR5-mediated ERK1/2 phosphorylation depends on NMDAR, which however exhibits a metabotropic way of function, since no ion influx through its ion channel is required. Furthermore, our results demonstrate that mGluR5 and mGluR5/NMDAR-evoked ERK1/2 activation correlates well with the mGluR5/NMDAR-evoked NR2B(Tyr1472) phosphorylation, since both phenomena coincide temporally, are Src dependent, and are both enabled by A2A Rs. This indicates a functional involvement of NR2B(Tyr1472) phosphorylation in the ERK1/2 activation. Our biochemical results are supported by electrophysiological data showing that in CA1 region of hippocampus, the theta burst stimulation (TBS)-induced long-term potentiation coincides temporally with an increase in ERK1/2 activation and both phenomena are dependent on the tripartite A2A , mGlu5, and NMDARs. Furthermore, we show that the dopamine D1 receptors evoked ERK1/2 activation as well as the NR2B(Tyr1472) phosphorylation are also regulated by endogenous adenosine and A2A Rs. In conclusion, our results highlight the A2A Rs as a crucial regulator not only for NMDAR responses, but also for regulating ERK1/2 signaling and its downstream pathways, leading to gene expression, synaptic plasticity, and memory consolidation.

A gradient of frequency-dependent synaptic properties along the longitudinal hippocampal axis.

BACKGROUND: The hippocampus is a functionally heterogeneous brain structure and specializations of the intrinsic neuronal network may crucially support the functional segregation along the longitudinal axis of the hippocampus. Short-term synaptic plasticity plays fundamental roles in information processing and may be importantly involved in diversifying the properties of local neuronal network along the hippocampus long axis. Therefore, we aimed to examine the properties of the cornu ammonis 1 (CA1) synapses along the entire dorsoventral axis of the rat hippocampus using field excitatory postsynaptic potentials from transverse rat hippocampal slices and a frequency stimulation paradigm. RESULTS: Applying a ten-pulse stimulus train at frequencies from 0.1 to 100 Hz to the Schaffer collaterals we found a gradually diversified pattern of frequency-dependent synaptic effects along the dorsoventral hippocampus axis. The first conditioned response was facilitated along the whole hippocampus for stimulus frequencies 10-40 Hz. However, steady-state responses or averaged responses generally ranged from maximum synaptic facilitation in the most dorsal segment of the hippocampus to maximum synaptic depression in the most ventral segment of the hippocampus. In particular, dorsal synapses facilitated for stimulus frequency up to 50 Hz while they depressed at higher frequencies (75-100 Hz). Facilitation at dorsal synapses was maximal at stimulus frequency of 20 Hz. On the contrary, the most ventral synapses showed depression regardless of the stimulus frequency, only displaying a transient facilitation at the beginning of 10-50 Hz stimulation. Importantly, the synapses in the medial hippocampus displayed a transitory behavior. Finally, as a whole the hippocampal synapses maximally facilitated at 20 Hz and increasingly depressed at 50-100 Hz. CONCLUSION: The short-term synaptic dynamics change gradually along the hippocampal long axis in a frequency-dependent fashion conveying distinct properties of information processing to successive segments of the structure, thereby crucially supporting functional segregation along the dorsoventral axis of the hippocampus.