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GABA B receptor activation underlies paired-pulse depression of polysynaptic EPSPs. A: GABA B receptor-mediated slow inhibitory postsynaptic potentials (IPSPs) are elicited by presynaptic fiber stimulation strengths that elicit polysynaptic EPSPs. The traces show superimposed postsynaptic responses (average of 3 responses) elicited by Schaffer collateral fiber stimulation before and after bath application of the GABA B receptor antagonist CGP55845 (5 M). Calibration bars are 5 mV and 50 ms. Right: peak amplitude of the slow IPSPs before (open bars) and after (filled bars) bath application of CGP55845 (n 7, asterisk, P 0.001 compared with control). B: examples of EPSPs evoked by pairs of presynaptic fiber stimulation pulses (interpulse interval 500 ms) in the same cell before (gray line) and after a 5-min bath application of 5 M CGP55845 (dark line). Calibration bars are 5 mV and 50 ms. C: summary of 8 experiments like that shown in B where paired-pulse depression of polysynaptic EPSPs was examined before and during bath application of 5 M CGP55845 (indicated by the bar).
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The existence of recurrent excitatory synapses between pyramidal cells in the hippocampal CA1 region has been known for some time yet little is known about activity-dependent forms of plasticity at these synapses. Here we demonstrate that under certain experimental conditions, Schaffer collateral/commissural fiber stimulation can elicit robust poly...
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Synapses between hippocampal interneurons are an important potential target for modulatory influences that could affect overall network behavior. We report that the selective group III metabotropic receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depresses GABAergic transmission to interneurons more than to pyramidal neurons. The L-AP4...
Citations
... As for excitatory back-projection from CA1 to CA3, none has yet been described (Witter, 2010). Within the CA1 itself there are also some recurrent connections, however, principal cells in CA1 mostly project towards the PCs of the subiculum, targeting both proximal and distal apical dendrites (Fink et al., 2007). Apart from the connections mentioned above, the hippocampus proper also receives inputs from other sources such as the nucleus reuniens (NR) in the thalamus which terminates in SLM and the amygdala whose collaterals are found in deeper layers like SO (Klausberger, 2009). ...
In an age where computational power and technological advances have allowed us the possibility to simulate whole brain regions, the data necessary for such models is in high demand. Currently available experimental data, however, is both sparse and non-uniform, due to the various sources it is extracted from and the different methods and technologies used for its procurement. The mouse hippocampus CA1 region is one of the most anatomically studied brain structures due to its relative simplicity and availability of transgenic mice. The structure itself is a window into the neural bases of cognition; representing the processing, storage and emotional flavouring of our episodic memories. A complete anatomical model, down to the cellular level of the mouse hippocampus, however, has not yet been simulated, with data scarcity being one of the main culprits for the delay. In this study, therefore, through an extensive literature review and data mining, the constituent glutamatergic and GABAergic neurons of the CA1 region of the mouse hippocampus were classified and quantified. By means of extensive calculations, the data has been streamlined and presented with laminar dorso-ventral accuracy. Such a quantitative knowledge-base is not only a requirement for data-driven, large-scale computational simulations but also acts to inspire and focus future experimental projects onto current gaps in the data thus aiming towards a more holistic histological profile of the mouse CA1 hippocampal region.
... However, D1R/D5R antagonists block norepinephrine and serotonergic receptors (5HT-2), the serotonin transporter, which expresses throughout the hippocampus, and other g-protein coupled receptors. Hicks et al., 1984;Ohlstein and Berkowitz, 1985;Fink et al., 2007;Zarrindast et al., 2011), obscuring a strong conclusion as to whether hippocampal D1R activation is truly required for spatial learning and memory. Our data, shows that the D1R primarily expresses in the DG of the hippocampus, but not CA3 or CA1 (Supporting Information Fig. 2), which is in agreement with previous findings (Fremeau et al., 1991;Mansour et al., 1992;Mu et al., 2011;Sariñana et al., 2014) However, a recent publication suggest that there is sparse D1R expression in the CA3 and CA1 hippocampal subfields, particularly in interneurons (Gangarossa et al., 2012). ...
Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1R- and D5R-specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory.
... However, D1R/D5R antagonists block norepinephrine and serotonergic receptors (5HT-2), the serotonin transporter, which expresses throughout the hippocampus, and other g-protein coupled receptors. Hicks et al., 1984;Ohlstein and Berkowitz, 1985;Fink et al., 2007;Zarrindast et al., 2011), obscuring a strong conclusion as to whether hippocampal D1R activation is truly required for spatial learning and memory. Our data, shows that the D1R primarily expresses in the DG of the hippocampus, but not CA3 or CA1 (Supporting Information Fig. 2), which is in agreement with previous findings (Fremeau et al., 1991;Mansour et al., 1992;Mu et al., 2011;Sariñana et al., 2014) However, a recent publication suggest that there is sparse D1R expression in the CA3 and CA1 hippocampal subfields, particularly in interneurons (Gangarossa et al., 2012). ...
Activation of the hippocampal dopamine 1-class receptors (D1R
and D5R) are implicated in contextual fear conditioning (CFC).
However, the specific role of the D1R versus D5R in hippocampal
dependent CFC has not been investigated. Generation of D1R- and
D5R-specific in situ hybridization probes showed that D1R and D5R
mRNA expression was greatest in the dentate gyrus (DG) of the
hippocampus. To identify the role of each receptor in CFC we
generated spatially restricted KO mice that lack either the D1R or
D5R in DG granule cells. DG D1R KOs displayed significant fear
memory deficits, whereas DG D5R KOs did not. Furthermore, D1R
KOs but not D5R KOs, exhibited generalized fear between two
similar but different contexts. In the familiar home cage context,
c-Fos expression was relatively low in the DG of control mice, and
it increased upon exposure to a novel context. This level of c-Fos
expression in the DG did not further increase when a footshock
was delivered in the novel context. In DG D1R KOs, DG c-Fos levels
in the home cage was higher than that of the control mice, but it
did not further increase upon exposure to a novel context and
remained at the same level upon a shock delivery. In contrast, the
levels of DG c-Fos expression was unaffected by the deletion of DG
D5R neither in the home cage nor upon a shock delivery. These results
suggest that DG D1Rs, but not D5Rs, contribute to the formation of
distinct contextual representations of novel environments.
... Individual basket cells can through divergent connections, however, drive the spike time of a group of PCs (Cobb et al., 1995). The recurrent excitation implemented in " Circuit 5 " is common in neocortical microcircuits (Silberberg and Markram, 2007 ) and, while not as common in CA1, there are a number of studies demonstrating their existence (Crépel et al., 1997; Aniksztejn et al., 2001; Fink et al., 2007). Feedback connections among CA1 PCs are prevalent in the developing brain but are rarely found in the adult hippocampus (Crépel et al., 1997). ...
... Deuchars and Thomson (1996) reported connections between CA1 PC in about 1% of their recorded pairs. Blocking inhibition, however, increased the likelihood of finding PC to PC connections in CA1 (Crépel et al., 1997; Fink et al., 2007). Lesions using kainate in rats also promote CA1 the appearance of PC connection recurrence (Perez et al., 1996). ...
... Lesions using kainate in rats also promote CA1 the appearance of PC connection recurrence (Perez et al., 1996). Feedback CA1 PC synapses are also special in terms of synaptic plasticity and activity history can convert CA1 from a parallel circuit to a network with sparse recurrence (Fink et al., 2007). Hence, the connection scenario of " Circuit 5 " is plausible in both neocortex and hippocampus (Cobb et al., 1995; Silberberg and Markram, 2007). ...
Synchronization among neurons is thought to arise from the interplay between excitation and inhibition; however, the connectivity rules that contribute to synchronization are still unknown. We studied these issues in hippocampal CA1 microcircuits using paired patch clamp recordings and real time computing. By virtually connecting a model interneuron with two pyramidal cells (PCs), we were able to test the importance of connectivity in synchronizing pyramidal cell activity. Our results show that a circuit with a nonreciprocal connection between pyramidal cells and no feedback from PCs to the virtual interneuron produced the greatest level of synchronization and mutual information between PC spiking activity. Moreover, we investigated the role of intrinsic membrane properties contributing to synchronization where the application of a specific ion channel blocker, ZD7288 dramatically impaired PC synchronization. Additionally, background synaptic activity, in particular arising from NMDA receptors, has a large impact on the synchrony observed in the aforementioned circuit. Our results give new insights to the basic connection paradigms of microcircuits that lead to coordination and the formation of assemblies.
... Successful isolation of GABA B mediated currents was tested through use of 2 μM CGP55845 (a specific GABA B receptor antagonist) which completely inhibited slow IPSCs within 5 minutes of perfusion (n=16). Likewise slow IPSCs were partially suppressed by GIRK channel blockers tertiapin-Q (100 nM, n=5, 55 ± 0.1% at 15 minutes) and SCH23390 (10 μM, n=6, 54 ± 0.1% at 12 minutes) (Fink, et al., 2007, Jelacic, et al., 2000, Kuzhikandathil and Oxford, 2002. Incomplete block of slow IPSCs by GIRK channel blockers may be due to heterogenous GABA B postsynaptic currents, partial block, or use dependence (Best, et al., 2007, Kanjhan, et al., 2005, Pham, et al., 1998, Tabata, et al., 2005. ...
GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABA(B)/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABA(B) and GABA(A) mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABA(B)/GABA(A) ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABA(B)/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABA(B) and GABA(A) inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice.
... After decapitation the brain was removed and put in an ice-cold (0-3° As noted above my experiments were performed in the presence of picrotoxin to block the GABA A -ergic transmission. When adding picrotoxin to adult slices 4 mM Ca 2+ and Mg 2+ is used in the perfusion fluid to lower the excitability of the neurones and thus prevent spontaneous activity (Wigström and Gustafsson, 1983; Fink et al., 2007). While such a high divalent ion concentrations may seem superfluous early in the 2 nd postnatal week when the GABA A receptor mediated transmission is still depolarizing, it may well be required for the slices from the P11-12 rats. ...
The glutamate synapse is by far the most common synapse in the brain and acts via postsynaptic AMPA, NMDA and mGlu receptors. During brain development there is a continuous production of these synapses where those partaking in activity resulting in neuronal activity are subsequently selected to establish an appropriate functional pattern of synaptic connectivity while those that do not are elimimated. Activity dependent synaptic plasticities, such as Hebbian induced long-term potentiation (LTP) and low frequency (1 Hz) induced long-term depression (LTD) have been considered to be of critical importance for this selection. However, in the neonatal brain the glutamate synapse displays a seemingly distinct plasticity in that even very low frequency stimulation (0.05-0.2 Hz) results in depression of the AMPA receptor mediated signaling and hence to possible synaptic elimination. The aim of this thesis was to investigate the relationship and interaction between this very low frequency induced plasticity and the more conventional forms of synaptic plasticity, such as mGlu receptor dependent LTD and NMDA receptor dependent LTP and LTD, using the neonatal rat hippocampal CA3-CA1 synapse as a model synapse. This thesis shows that very low frequency induced depression is related to NMDA receptor dependent LTD. While elicited even during NMDA receptor blockade, this plasticity is facilitated and stabilized by NMDA receptor activity and largely occludes NMDA receptor dependent LTD. Surprisingly, considering their role in conventionally induced LTD, mGlu receptors were not found to participate in either the very low frequency induced depression or in low frequency induced long-lasting depression. A preceding LTP-inducing Hebbian stimulation was found to only partially stabilize against the very low frequency induced depression, and possibly also only in a temporary manner. In conclusion; during brain development glutamate activated AMPA receptors are very easily lost upon activation rendering these synapses AMPA silent, and Hebbian activity will only temporarily rescue them from AMPA silence. Thus, synapses in the developing brain will maintain their AMPA signaling only by more or less continuous participation in cooperative neuronal activity, synaptic activity outside this context leading to AMPA silencing and possible elimination.
... These results suggested the involvement of G-proteins in activation of the NPY-activated K + current, and blockers of Gprotein-coupled inwardly rectifying potassium channels (GIRK) were tested next. Bath application of SCH23390 (15 μM), a potent GIRK blocker (Kuzhikandathil and Oxford, 2002;Fink et al., 2007), reduced NPY reaction by 86% (n = 6) (Fig. 4). Similar results were obtained by local superfusion of Ba 2+ (100 μM-1 mM in pipette) near the recording site during near-maximal responses to NPY (0.5 μM) which rapidly reduced the amplitude of the outward current by 78% (n = 6; data not shown), suggesting that the hyperpolarizing actions of NPY in LA projection neurons may be attributable to activation of G-proteinlinked inwardly rectifying potassium channels in the postsynaptic compartment. ...
Neuropeptide Y (NPY) reduces anxiety-related behavior in various animal models. Since activity in the lateral amygdala (LA) seems crucial for fear expression of behavior, we studied the mechanisms of NPY in LA projection neurons using whole-cell patch-clamp recordings in slices of the rat amygdala in vitro. Application of NPY activated a membrane K+ current with inwardly rectifying properties in 92% of tested neurons. Pharmacological properties were indicative of mediation via Y1 receptors. Nonhydrolyzable analogues of guanine nucleotides and SCH23390 blocked the NPY-activated current. Single-cell RT-PCR demonstrated expression of G-protein-coupled inwardly rectifying K+ channel (GIRK) subunits GIRK1, GIRK2 and GIRK3, suggesting mediation of the NPY response through GIRK type channels. The NPY-activated current depressed action potential firing in LA projection neurons, through membrane hyperpolarization and decreased input resistance. Functionally, the dampening of excitability in projection neurons of the amygdala may contribute to the decrease in anxiogenic behavior during action of NPY.
Synaptic plasticity in the hippocampus underlies episodic memory formation, with dorsal hippocampus being instrumental for spatial memory whereas ventral hippocampus is crucial for emotional learning.
Here, we studied how GABAergic inhibition regulates physiologi-cally relevant low repeat spike timing-dependent LTP (t-LTP) at Schaffer collateral-CA1 synapses along the dorsoventral hippo-campal axis. We used two t-LTP protocols relying on only 6 repeats of paired spike-firing in pre- and postsynaptic cells within 10 s that differ in postsynaptic firing patterns. GABA-A receptor mechanisms played a greater role in blocking 6x 1:1 t-LTP that recruits single postsynaptic action potentials. 6x 1:4 t-LTP that depends on postsynaptic burst-firing unexpectedly required intact GABA-B receptor signaling. The magnitude of both t-LTP-forms decreased along the dorsoventral axis, despite increasing excitability and basal synaptic strength in this direction. This suggests that GABAergic inhibition contributes to the distinct roles of dorsal and ventral hippocampus in memory formation.
