Editorial on the Research Topic Dopaminergic control of experience encoding, memory and cognition... more Editorial on the Research Topic Dopaminergic control of experience encoding, memory and cognition Dopamine plays a central and multifaceted role in several cognitive functions. It is synthesized and released by dopaminergic neurons that originate from different brain regions, mainly the ventral tegmental area (VTA) and the substantia nigra, and innervate several brain areas, including the nucleus accumbens, amygdala, medial prefrontal cortex, striatum, and hippocampus . Dopamine exerts its effects through two major types of receptors: D1/D5 and D2-like receptors, which activate distinct signaling pathways and modulate synaptic plasticity and neuronal activity. The importance of dopamine in brain functioning is underscored by its well-known involvement in several neurological and psychiatric disorders, such as Parkinson's disease, schizophrenia, depression, and addiction . Moreover, dopamine-based treatments often disrupt the balance of the system and cause unwanted side effects in patients. Recent research has shed light on the broad involvement of dopamine in the normal functioning of the brain. Dopamine plays an intricate role in the encoding of experiences, a process that intersects with learning and memory, decision-making, novelty processing, motivation, sleep, and attention. This Research Topic addresses these issues with a focus on learning and memory and presents relevant findings that advance our understanding of the role of dopamine in the brain. How the different dopamine receptors affect brain functions is not well understood and was one of the questions addressed in the current Research Topic. Matzel and Sauce discuss that the balance of D1/5R and D2R with regard to their expression density, activity state, and availability may play a key role in attention and working memory, and in variations in intelligence. In line with this idea, Hagena et al. demonstrate that two mouse strains (CaOlaHsd and C57Bl6) have different patterns of D1/5R expression in the hippocampus and found that such altered balance results in changes in dopaminergic-dependent synaptic plasticity. Thus, differences in D1/D5R expression may explain, in part, strain-dependent variations in synaptic plasticity in the murine hippocampus. The complex relationship between reward, motivation, dopamine, and learning prediction error coding remains a challenging question. The contribution by de Oliveira Alves et al. examines the influence
The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5)... more The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (>24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes.
Wir haben untersucht, ob die Frequenz Faszilitierung, eine charakteristische Eigenschaft der Moos... more Wir haben untersucht, ob die Frequenz Faszilitierung, eine charakteristische Eigenschaft der Moosfaser-CA3 Synapse, nachhaltige funktionelle Konsequenzen für die Verarbeitung von Informationen hat. Ein Teil dieser Arbeit beschäftigt sich mit Adenosin A\(_{1}\) Rezeptoren an der Moosfaser-Synapse, da die Aktivierung von diesen Rezeptoren durch Adenosin zur Frequenz Faszilitierung beiträgt. Das noradrenerge System spielt eine wichtige Rolle in der Aufnahme, der Kodierung und dem Wiederabrufen räumlicher Informationen und ist involviert in molekularen Prozessen, die synaptische Eigenschaften, insbesondere die niedrige Freisetzungswahrscheinlichkeit von Transmittern an der Moosfaser-CA3 Synapse, vermitteln. Neben den Moosfasern erhält die CA3 Region auch assozial-commissurale Informationen von anderen CA3 Neuronen. Beide Projektionen leiten wahrscheinlich verschiedene Arten räumlicher Information weiter und sind daher von besonderem Interesse.In this work we examined whether frequency f...
The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is specie... more The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is species-dependent: rats express more robust and more prolonged LTP in response to a broader afferent frequency range than mice. The C57Bl/6 mouse is an extremely popular murine strain used in studies of hippocampal synaptic plasticity and spatial learning. Recently it was reported that it expresses impoverished LTP compared to other murine strains. Given the important role of the dopamine D1/D5 receptor (D1/D5R) in the maintenance of LTP and in memory consolidation, we explored to what extent strain-dependent differences in LTP in mice are determined by differences in D1/D5R-control. In CaOlaHsd mice, robust LTP was induced that lasted for over 24 h and which was significantly greater in magnitude than LTP induced in C57Bl/6 mice. Intracerebral treatment with a D1/D5R-antagonist (SCH23390) prevented both the early and late phase of LTP in CaOlaHsd mice, whereas only late-LTP was impaired in C57Bl/6 mice. Treatment with a D1/D5R-agonist (Chloro-PB) facilitated short-term potentiation (STP) into LTP (> 24 h) in both strains, whereby effects became evident earlier in CaOlaHsd compared to C57Bl/6 mice. Immunohistochemical analysis revealed a significantly higher expression of D1-receptors in the stratum lacunosum moleculare of CaOlaHsd compared to C57Bl/6 mice. These findings highlight differences in D1/D5R-dependent regulation of straindependent variations in hippocampal LTP in C57Bl/6 and CaOlaHsd mice, that may be mediated, in part, by differences in the expression of D1R in the hippocampus.
In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex... more In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromise...
DAB-stained coronary sections showing expression of GluN1, GluN2A, GluN2B and GABAA expression in... more DAB-stained coronary sections showing expression of GluN1, GluN2A, GluN2B and GABAA expression in CBA/J mice compared to CBA/CaOlaHsd mice.
Frequency facilitation (FF), comprising a rapid and multiple-fold increase in the magnitude of ev... more Frequency facilitation (FF), comprising a rapid and multiple-fold increase in the magnitude of evoked field potentials, is elicited by low-frequency stimulation (LFS) at mossy fiber--CA3 synapses. Here, we show that in freely behaving rats, FF reliably occurs in response to 1 and 2Hz but not in response to 0.25-, 0.3-, or 0.5-Hz LFS. Strikingly, prolonged (~600 s) FF was tightly correlated to the induction of long-term depression (LTD) in freely moving animals. Although LFS at 2 Hz elicited unstable FF and unstable LTD, application of LFS at 1 Hz elicited pronounced FF, as well as robust LTD that persisted for over 24 h. This correlation of prolonged FF with LTD was absent at stimulation frequencies that did not induce FF. The adenosine-A1 receptor appears to participate in these effects: Application of adenosine-A1, but not adenosine-A3, receptor antagonists enhanced mossy fiber synaptic transmission and occluded FF. Furthermore, adenosine-A1 receptor antagonism resulted in more st...
In the hippocampus, the metabotropic glutamate (mGlu) receptor, mGlu5, plays a very prominent rol... more In the hippocampus, the metabotropic glutamate (mGlu) receptor, mGlu5, plays a very prominent role in synaptic information storage and memory. This receptor enables persistent (>24 h) forms of synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), and is also required for plasticity forms that are directly modulated by spatial learning. mGlu5 supports hippocampal neuronal oscillations that occur during synaptic plasticity events, supports the stabilization of place fields, and regulates the direction of change in synaptic weights in specific synaptic subcompartments of the hippocampus. Furthermore, dysfunctions in this receptor are associated with potent disturbances of hippocampus-dependent cognition. We propose that the mGlu5 receptor lies at the hub of hippocampal information processing and is pivotal to the accurate, long-term, and reliable acquisition and encoding of new spatial experiences and cognitive representations.
The encoding of spatial representations is enabled by synaptic plasticity. The entorhinal cortex ... more The encoding of spatial representations is enabled by synaptic plasticity. The entorhinal cortex sends information to the hippocampus via the lateral (LPP) and medial perforant (MPP) paths that transfer egocentric item-related and allocentric spatial information, respectively. To what extent LPP and MPP information-relay results in different homosynaptic synaptic plasticity responses is unclear. We examined the frequency dependency (at 1, 5, 10, 50, 100, 200 Hz) of long-term potentiation (LTP) and long-term depression (LTD) at MPP and LPP synapses in the dentate gyrus (DG) of freely behaving adult rats. We report that whereas the MPP-DG synapses exhibit a predisposition toward the expression of LTP, LPP-DG synapses prefer to express synaptic depression. The divergence of synaptic plasticity responses is most prominent at afferent frequencies of 5, 100, Hz and 200 Hz. Priming with 10 or 50 Hz significantly modified the subsequent plasticity response in a frequency-dependent manner, but failed to change the preferred direction of change in synaptic strength of MPP and LPP synapses. Evaluation of the expression of GluN1, GluN2A, or GluN2B subunits of the NMDA receptor revealed equivalent expression in the outer and middle thirds of the molecular layer where LPP and MPP inputs convene, respectively, thus excluding NMDA receptors as a substrate for the frequency-dependent differences in bidirectional plasticity. These findings demonstrate that the LPP and MPP inputs to the DG enable differentiated and distinct forms of synaptic plasticity in response to the same afferent frequencies. Effects are extremely robust and resilient to metaplastic priming. These properties may support the functional differentiation of allocentric and item information provided to the DG by the MPP and LPP, respectively, that has been proposed by others. We propose that allocentric spatial information, conveyed by the MPP is Jens Collitti-Klausnitzer and Hardy Hagena are joint first authors.
Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiati... more Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5-HT 4-receptor contributes to processes underlying cognition. It was previously shown that in the CA1-region, 5-HT 4-receptors regulate the frequency-response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a hm-frequency), will result in LTP or LTD, when given in the presence of a 5-HT 4-agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5-HT 4-receptors do not influence responses generated at hm-frequencies, but activation of 5-HT 4-receptors prevents persistent LTD in mossy fiber (mf)-CA3, or perforant path-DG synapses. Furthermore, the regulation by 5-HT 4-receptors of LTP is subfield-specific: 5-HT 4-receptor-activation prevents mf-CA3-LTP, but does not strongly affect DG-potentiation. These data suggest that 5-HT 4-receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf-CA3 synapses. Thus, 5-HT 4-receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience-dependent encoding. V
Cerebral cortex (New York, N.Y. : 1991), Jan 24, 2016
Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. ... more Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 25, 2015
Within the hippocampus, different kinds of spatial experience determine the direction of change o... more Within the hippocampus, different kinds of spatial experience determine the direction of change of synaptic weights. Synaptic plasticity resulting from such experience may enable memory encoding. The CA3 region is very striking in this regard: due to the distinct molecular properties of the mossy fiber (MF) and associational-commissural (AC) synapses, it is believed that they enable working memory and pattern completion. The question arises, however, as to how information reaching these synapses results in differentiated encoding. Given its crucial role in enabling persistent synaptic plasticity in other hippocampal subfields, we speculated that the metabotropic glutamate receptor mGlu5 may regulate information encoding at MF and AC synapses. Here, we show that antagonism of mGlu5 inhibits LTP, but not LTD at MF synapses of freely behaving adult rats. Conversely, mGlu5 antagonism prevents LTD but not LTP at AC-CA3 synapses. This suggests that, under conditions in which mGlu5 is acti...
Frequency facilitation, elicited by low-frequency stimulation (LFS) is a specific property of mos... more Frequency facilitation, elicited by low-frequency stimulation (LFS) is a specific property of mossy fiber-CA3 synapses. Although it has been widely described in vitro, no evidence as yet exists as to whether this phenomenon occurs in vivo. Here, we show that, in freely behaving rats, frequency facilitation at mossy fiber-CA3 synapses consistently occurs in response to LFS (1 Hz). Extracellular adenosine regulates presynaptic neurotransmitter release via action on adenosine A1 receptors and contributes to frequency facilitation in vitro. We investigated whether adenosine A1 receptors mediate frequency facilitation in freely behaving animals. The adenosine A1 receptor antagonists, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and phenylxanthine, markedly enhanced mossy fiber synaptic transmission and significantly occluded frequency facilitation. Evoked responses were suppressed by application of the group II metabotropic glutamate receptor agonist (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine (DCG-IV), in line with the known sensitivity of mossy fiber-CA3 synapses to this agent. By comparison, neither frequency facilitation, effects of the adenosine A1 antagonists, nor effects of DCG-IV were evident at either perforant path-dentate gyrus synapses or commissural/associational CA3 synapses in vivo. These data support that frequency facilitation is an intrinsic property of information storage processes at mossy fiber-CA3 synapses in the intact animal and that frequency facilitation in vivo may be mediated by regulation of the adenosine A1 receptor.
Long-term potentiation (LTP) and long-term depression (LTD) are two mechanisms involved in the lo... more Long-term potentiation (LTP) and long-term depression (LTD) are two mechanisms involved in the long-term storage of information in hippocampal synapses. In the hippocampal CA1 region, the late phases of LTP and LTD are protein-synthesis dependent. In the dentate gyrus, late-LTP but not LTD requires protein synthesis. The protein synthesis-dependency of persistent plasticity at CA3 synapses has not yet been characterized. Here, the roles of protein transcription and translation at mossy fiber (mf) and associational/commissural (AC)-synapses were studied in freely behaving rats. In control animals, low-frequency stimulation (LFS) evoked robust LTD (>24 h), whereas high-frequency stimulation (HFS) elicited robust LTP (>24 h) at both mf-CA3 and AC-CA3 synapses. Translation inhibitors prevented early and late phases of LTP and LTD at mf-CA3 synapses. In contrast, at AC-CA3 synapses, translation inhibitors prevented intermediate/late-LTP and late-LTD only. Transcription effects were also synapse-specific: whereas transcription inhibitors inhibited late-LTP and late-LTD (>3 h) at mf-CA3 synapses, at AC-CA3 synapses, protein transcription affected early-LTP and late-LTD. These results show that the AC-CA3 and mf-CA3 synapses display different properties in terms of their protein synthesis dependency, suggesting different roles in the processing of short-and long term synaptic plasticity.
Learning-facilitated plasticity refers to hippocampal synaptic plasticity that is facilitated by ... more Learning-facilitated plasticity refers to hippocampal synaptic plasticity that is facilitated by novel spatial learning events. Both long-term potentiation (LTP) and long-term depression (LTD) are facilitated by novel hippocampus-dependent learning. This has important ramifications for our understanding of how the hippocampus encodes memory. One structure that is rarely studied in vivo, but is believed to be crucially important for working and long-term memory processing is the hippocampal CA3 region. Whereas learning-facilitated plasticity has been described in this structure, the mechanisms underlying this phenomenon have not been explored. The noradrenergic system plays an important role in arousal and qualification of new information as salient. It regulates synaptic plasticity in the dentate gyrus and CA1, but nothing is known about the regulation by the noradrenergic system of synaptic plasticity in the CA3 region. We explored whether β-adrenergic receptors contribute to learning-facilitated plasticity at mossy fiber (mf)-CA3 synapses of behaving rats. We found that receptor antagonism had no effect on basal synaptic transmission, short-term potentiation (STP), short-term depression, LTP, or LTD, that were electrically induced by patterned afferent stimulation. We found, however, that both learning-facilitated LTP and LTD were prevented by antagonism of β-adrenergic receptors, whereas the agonist isoproterenol facilitated STP into LTP. Thus, learning-facilitated and electrically-induced plasticity may not share the same prerequisites. These results support that the mf synapse engages in a distinct aspect of encoding of spatial information that involves both LTP and LTD. Furthermore, changes in arousal that are coupled to new learning are associated with activation of hippocampal β-adrenergic receptors that in turn comprise a key element in this type of information acquisition and processing by the CA3 region.
Subregion-dependent differences in the role of the hippocampus in information processing exist. R... more Subregion-dependent differences in the role of the hippocampus in information processing exist. Recently, it has emerged that a special relationship exists between the expression of persistent forms of synaptic plasticity in hippocampal subregions and the encoding of different types of spatial information. Little is known about this type of information processing at CA3 synapses. We report that in freely behaving rats, long-term potentiation (LTP) is facilitated at both mossy fiber (mf)-CA3 and commissural-associational (AC)-CA3 synapses by exploration of a novel (empty) environment. Exploration of large spatial landmarks facilitates long-term depression (LTD) at mf-CA3 synapses and impairs synaptic depression at AC-CA3 synapses. Novel exploration of small environmental features does not facilitate LTD at mf synapses but facilitates persistent LTD at AC synapses. Thus, depending on the quality of the information synaptic plasticity at AC-CA3 and mf-CA3 synapses is differentially modulated. These data suggest that expression of LTP as a result of environmental change is a common property of hippocampal synapses. However, LTD at mf synapses or AC synapses may subserve distinct and separate functions within the CA3 region.
Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct prope... more 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 (>24 h) 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 the spatial experience effe...
Editorial on the Research Topic Dopaminergic control of experience encoding, memory and cognition... more Editorial on the Research Topic Dopaminergic control of experience encoding, memory and cognition Dopamine plays a central and multifaceted role in several cognitive functions. It is synthesized and released by dopaminergic neurons that originate from different brain regions, mainly the ventral tegmental area (VTA) and the substantia nigra, and innervate several brain areas, including the nucleus accumbens, amygdala, medial prefrontal cortex, striatum, and hippocampus . Dopamine exerts its effects through two major types of receptors: D1/D5 and D2-like receptors, which activate distinct signaling pathways and modulate synaptic plasticity and neuronal activity. The importance of dopamine in brain functioning is underscored by its well-known involvement in several neurological and psychiatric disorders, such as Parkinson's disease, schizophrenia, depression, and addiction . Moreover, dopamine-based treatments often disrupt the balance of the system and cause unwanted side effects in patients. Recent research has shed light on the broad involvement of dopamine in the normal functioning of the brain. Dopamine plays an intricate role in the encoding of experiences, a process that intersects with learning and memory, decision-making, novelty processing, motivation, sleep, and attention. This Research Topic addresses these issues with a focus on learning and memory and presents relevant findings that advance our understanding of the role of dopamine in the brain. How the different dopamine receptors affect brain functions is not well understood and was one of the questions addressed in the current Research Topic. Matzel and Sauce discuss that the balance of D1/5R and D2R with regard to their expression density, activity state, and availability may play a key role in attention and working memory, and in variations in intelligence. In line with this idea, Hagena et al. demonstrate that two mouse strains (CaOlaHsd and C57Bl6) have different patterns of D1/5R expression in the hippocampus and found that such altered balance results in changes in dopaminergic-dependent synaptic plasticity. Thus, differences in D1/D5R expression may explain, in part, strain-dependent variations in synaptic plasticity in the murine hippocampus. The complex relationship between reward, motivation, dopamine, and learning prediction error coding remains a challenging question. The contribution by de Oliveira Alves et al. examines the influence
The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5)... more The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (>24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes.
Wir haben untersucht, ob die Frequenz Faszilitierung, eine charakteristische Eigenschaft der Moos... more Wir haben untersucht, ob die Frequenz Faszilitierung, eine charakteristische Eigenschaft der Moosfaser-CA3 Synapse, nachhaltige funktionelle Konsequenzen für die Verarbeitung von Informationen hat. Ein Teil dieser Arbeit beschäftigt sich mit Adenosin A\(_{1}\) Rezeptoren an der Moosfaser-Synapse, da die Aktivierung von diesen Rezeptoren durch Adenosin zur Frequenz Faszilitierung beiträgt. Das noradrenerge System spielt eine wichtige Rolle in der Aufnahme, der Kodierung und dem Wiederabrufen räumlicher Informationen und ist involviert in molekularen Prozessen, die synaptische Eigenschaften, insbesondere die niedrige Freisetzungswahrscheinlichkeit von Transmittern an der Moosfaser-CA3 Synapse, vermitteln. Neben den Moosfasern erhält die CA3 Region auch assozial-commissurale Informationen von anderen CA3 Neuronen. Beide Projektionen leiten wahrscheinlich verschiedene Arten räumlicher Information weiter und sind daher von besonderem Interesse.In this work we examined whether frequency f...
The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is specie... more The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is species-dependent: rats express more robust and more prolonged LTP in response to a broader afferent frequency range than mice. The C57Bl/6 mouse is an extremely popular murine strain used in studies of hippocampal synaptic plasticity and spatial learning. Recently it was reported that it expresses impoverished LTP compared to other murine strains. Given the important role of the dopamine D1/D5 receptor (D1/D5R) in the maintenance of LTP and in memory consolidation, we explored to what extent strain-dependent differences in LTP in mice are determined by differences in D1/D5R-control. In CaOlaHsd mice, robust LTP was induced that lasted for over 24 h and which was significantly greater in magnitude than LTP induced in C57Bl/6 mice. Intracerebral treatment with a D1/D5R-antagonist (SCH23390) prevented both the early and late phase of LTP in CaOlaHsd mice, whereas only late-LTP was impaired in C57Bl/6 mice. Treatment with a D1/D5R-agonist (Chloro-PB) facilitated short-term potentiation (STP) into LTP (> 24 h) in both strains, whereby effects became evident earlier in CaOlaHsd compared to C57Bl/6 mice. Immunohistochemical analysis revealed a significantly higher expression of D1-receptors in the stratum lacunosum moleculare of CaOlaHsd compared to C57Bl/6 mice. These findings highlight differences in D1/D5R-dependent regulation of straindependent variations in hippocampal LTP in C57Bl/6 and CaOlaHsd mice, that may be mediated, in part, by differences in the expression of D1R in the hippocampus.
In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex... more In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromise...
DAB-stained coronary sections showing expression of GluN1, GluN2A, GluN2B and GABAA expression in... more DAB-stained coronary sections showing expression of GluN1, GluN2A, GluN2B and GABAA expression in CBA/J mice compared to CBA/CaOlaHsd mice.
Frequency facilitation (FF), comprising a rapid and multiple-fold increase in the magnitude of ev... more Frequency facilitation (FF), comprising a rapid and multiple-fold increase in the magnitude of evoked field potentials, is elicited by low-frequency stimulation (LFS) at mossy fiber--CA3 synapses. Here, we show that in freely behaving rats, FF reliably occurs in response to 1 and 2Hz but not in response to 0.25-, 0.3-, or 0.5-Hz LFS. Strikingly, prolonged (~600 s) FF was tightly correlated to the induction of long-term depression (LTD) in freely moving animals. Although LFS at 2 Hz elicited unstable FF and unstable LTD, application of LFS at 1 Hz elicited pronounced FF, as well as robust LTD that persisted for over 24 h. This correlation of prolonged FF with LTD was absent at stimulation frequencies that did not induce FF. The adenosine-A1 receptor appears to participate in these effects: Application of adenosine-A1, but not adenosine-A3, receptor antagonists enhanced mossy fiber synaptic transmission and occluded FF. Furthermore, adenosine-A1 receptor antagonism resulted in more st...
In the hippocampus, the metabotropic glutamate (mGlu) receptor, mGlu5, plays a very prominent rol... more In the hippocampus, the metabotropic glutamate (mGlu) receptor, mGlu5, plays a very prominent role in synaptic information storage and memory. This receptor enables persistent (>24 h) forms of synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), and is also required for plasticity forms that are directly modulated by spatial learning. mGlu5 supports hippocampal neuronal oscillations that occur during synaptic plasticity events, supports the stabilization of place fields, and regulates the direction of change in synaptic weights in specific synaptic subcompartments of the hippocampus. Furthermore, dysfunctions in this receptor are associated with potent disturbances of hippocampus-dependent cognition. We propose that the mGlu5 receptor lies at the hub of hippocampal information processing and is pivotal to the accurate, long-term, and reliable acquisition and encoding of new spatial experiences and cognitive representations.
The encoding of spatial representations is enabled by synaptic plasticity. The entorhinal cortex ... more The encoding of spatial representations is enabled by synaptic plasticity. The entorhinal cortex sends information to the hippocampus via the lateral (LPP) and medial perforant (MPP) paths that transfer egocentric item-related and allocentric spatial information, respectively. To what extent LPP and MPP information-relay results in different homosynaptic synaptic plasticity responses is unclear. We examined the frequency dependency (at 1, 5, 10, 50, 100, 200 Hz) of long-term potentiation (LTP) and long-term depression (LTD) at MPP and LPP synapses in the dentate gyrus (DG) of freely behaving adult rats. We report that whereas the MPP-DG synapses exhibit a predisposition toward the expression of LTP, LPP-DG synapses prefer to express synaptic depression. The divergence of synaptic plasticity responses is most prominent at afferent frequencies of 5, 100, Hz and 200 Hz. Priming with 10 or 50 Hz significantly modified the subsequent plasticity response in a frequency-dependent manner, but failed to change the preferred direction of change in synaptic strength of MPP and LPP synapses. Evaluation of the expression of GluN1, GluN2A, or GluN2B subunits of the NMDA receptor revealed equivalent expression in the outer and middle thirds of the molecular layer where LPP and MPP inputs convene, respectively, thus excluding NMDA receptors as a substrate for the frequency-dependent differences in bidirectional plasticity. These findings demonstrate that the LPP and MPP inputs to the DG enable differentiated and distinct forms of synaptic plasticity in response to the same afferent frequencies. Effects are extremely robust and resilient to metaplastic priming. These properties may support the functional differentiation of allocentric and item information provided to the DG by the MPP and LPP, respectively, that has been proposed by others. We propose that allocentric spatial information, conveyed by the MPP is Jens Collitti-Klausnitzer and Hardy Hagena are joint first authors.
Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiati... more Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5-HT 4-receptor contributes to processes underlying cognition. It was previously shown that in the CA1-region, 5-HT 4-receptors regulate the frequency-response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a hm-frequency), will result in LTP or LTD, when given in the presence of a 5-HT 4-agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5-HT 4-receptors do not influence responses generated at hm-frequencies, but activation of 5-HT 4-receptors prevents persistent LTD in mossy fiber (mf)-CA3, or perforant path-DG synapses. Furthermore, the regulation by 5-HT 4-receptors of LTP is subfield-specific: 5-HT 4-receptor-activation prevents mf-CA3-LTP, but does not strongly affect DG-potentiation. These data suggest that 5-HT 4-receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf-CA3 synapses. Thus, 5-HT 4-receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience-dependent encoding. V
Cerebral cortex (New York, N.Y. : 1991), Jan 24, 2016
Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. ... more Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 25, 2015
Within the hippocampus, different kinds of spatial experience determine the direction of change o... more Within the hippocampus, different kinds of spatial experience determine the direction of change of synaptic weights. Synaptic plasticity resulting from such experience may enable memory encoding. The CA3 region is very striking in this regard: due to the distinct molecular properties of the mossy fiber (MF) and associational-commissural (AC) synapses, it is believed that they enable working memory and pattern completion. The question arises, however, as to how information reaching these synapses results in differentiated encoding. Given its crucial role in enabling persistent synaptic plasticity in other hippocampal subfields, we speculated that the metabotropic glutamate receptor mGlu5 may regulate information encoding at MF and AC synapses. Here, we show that antagonism of mGlu5 inhibits LTP, but not LTD at MF synapses of freely behaving adult rats. Conversely, mGlu5 antagonism prevents LTD but not LTP at AC-CA3 synapses. This suggests that, under conditions in which mGlu5 is acti...
Frequency facilitation, elicited by low-frequency stimulation (LFS) is a specific property of mos... more Frequency facilitation, elicited by low-frequency stimulation (LFS) is a specific property of mossy fiber-CA3 synapses. Although it has been widely described in vitro, no evidence as yet exists as to whether this phenomenon occurs in vivo. Here, we show that, in freely behaving rats, frequency facilitation at mossy fiber-CA3 synapses consistently occurs in response to LFS (1 Hz). Extracellular adenosine regulates presynaptic neurotransmitter release via action on adenosine A1 receptors and contributes to frequency facilitation in vitro. We investigated whether adenosine A1 receptors mediate frequency facilitation in freely behaving animals. The adenosine A1 receptor antagonists, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and phenylxanthine, markedly enhanced mossy fiber synaptic transmission and significantly occluded frequency facilitation. Evoked responses were suppressed by application of the group II metabotropic glutamate receptor agonist (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine (DCG-IV), in line with the known sensitivity of mossy fiber-CA3 synapses to this agent. By comparison, neither frequency facilitation, effects of the adenosine A1 antagonists, nor effects of DCG-IV were evident at either perforant path-dentate gyrus synapses or commissural/associational CA3 synapses in vivo. These data support that frequency facilitation is an intrinsic property of information storage processes at mossy fiber-CA3 synapses in the intact animal and that frequency facilitation in vivo may be mediated by regulation of the adenosine A1 receptor.
Long-term potentiation (LTP) and long-term depression (LTD) are two mechanisms involved in the lo... more Long-term potentiation (LTP) and long-term depression (LTD) are two mechanisms involved in the long-term storage of information in hippocampal synapses. In the hippocampal CA1 region, the late phases of LTP and LTD are protein-synthesis dependent. In the dentate gyrus, late-LTP but not LTD requires protein synthesis. The protein synthesis-dependency of persistent plasticity at CA3 synapses has not yet been characterized. Here, the roles of protein transcription and translation at mossy fiber (mf) and associational/commissural (AC)-synapses were studied in freely behaving rats. In control animals, low-frequency stimulation (LFS) evoked robust LTD (>24 h), whereas high-frequency stimulation (HFS) elicited robust LTP (>24 h) at both mf-CA3 and AC-CA3 synapses. Translation inhibitors prevented early and late phases of LTP and LTD at mf-CA3 synapses. In contrast, at AC-CA3 synapses, translation inhibitors prevented intermediate/late-LTP and late-LTD only. Transcription effects were also synapse-specific: whereas transcription inhibitors inhibited late-LTP and late-LTD (>3 h) at mf-CA3 synapses, at AC-CA3 synapses, protein transcription affected early-LTP and late-LTD. These results show that the AC-CA3 and mf-CA3 synapses display different properties in terms of their protein synthesis dependency, suggesting different roles in the processing of short-and long term synaptic plasticity.
Learning-facilitated plasticity refers to hippocampal synaptic plasticity that is facilitated by ... more Learning-facilitated plasticity refers to hippocampal synaptic plasticity that is facilitated by novel spatial learning events. Both long-term potentiation (LTP) and long-term depression (LTD) are facilitated by novel hippocampus-dependent learning. This has important ramifications for our understanding of how the hippocampus encodes memory. One structure that is rarely studied in vivo, but is believed to be crucially important for working and long-term memory processing is the hippocampal CA3 region. Whereas learning-facilitated plasticity has been described in this structure, the mechanisms underlying this phenomenon have not been explored. The noradrenergic system plays an important role in arousal and qualification of new information as salient. It regulates synaptic plasticity in the dentate gyrus and CA1, but nothing is known about the regulation by the noradrenergic system of synaptic plasticity in the CA3 region. We explored whether β-adrenergic receptors contribute to learning-facilitated plasticity at mossy fiber (mf)-CA3 synapses of behaving rats. We found that receptor antagonism had no effect on basal synaptic transmission, short-term potentiation (STP), short-term depression, LTP, or LTD, that were electrically induced by patterned afferent stimulation. We found, however, that both learning-facilitated LTP and LTD were prevented by antagonism of β-adrenergic receptors, whereas the agonist isoproterenol facilitated STP into LTP. Thus, learning-facilitated and electrically-induced plasticity may not share the same prerequisites. These results support that the mf synapse engages in a distinct aspect of encoding of spatial information that involves both LTP and LTD. Furthermore, changes in arousal that are coupled to new learning are associated with activation of hippocampal β-adrenergic receptors that in turn comprise a key element in this type of information acquisition and processing by the CA3 region.
Subregion-dependent differences in the role of the hippocampus in information processing exist. R... more Subregion-dependent differences in the role of the hippocampus in information processing exist. Recently, it has emerged that a special relationship exists between the expression of persistent forms of synaptic plasticity in hippocampal subregions and the encoding of different types of spatial information. Little is known about this type of information processing at CA3 synapses. We report that in freely behaving rats, long-term potentiation (LTP) is facilitated at both mossy fiber (mf)-CA3 and commissural-associational (AC)-CA3 synapses by exploration of a novel (empty) environment. Exploration of large spatial landmarks facilitates long-term depression (LTD) at mf-CA3 synapses and impairs synaptic depression at AC-CA3 synapses. Novel exploration of small environmental features does not facilitate LTD at mf synapses but facilitates persistent LTD at AC synapses. Thus, depending on the quality of the information synaptic plasticity at AC-CA3 and mf-CA3 synapses is differentially modulated. These data suggest that expression of LTP as a result of environmental change is a common property of hippocampal synapses. However, LTD at mf synapses or AC synapses may subserve distinct and separate functions within the CA3 region.
Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct prope... more 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 (>24 h) 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 the spatial experience effe...
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Papers by Hardy Hagena