Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro

The excitatory action of GABA is considered to be a hallmark of the developing nervous system. However, in immature brain slices, excitatory GABA actions may be secondary to neuronal injury during slice preparation. Here, we explored GABA actions in the rodent intact hippocampal preparations and at different depths of hippocampal slices during the early postnatal period (post-natal days [P] 1- 7). We found that in the intact hippocampus at P1-3: (i) GABA exerts depolarizing action as seen in cell-attached single GABA(A) channel recordings; (ii) GABA(A) receptor (GABA(A)-R) agonist isoguvacine and synaptic activation of the GABA(A)- Rs increase the frequency of multiple unit activity (MUA) and the frequency of the network-driven Giant Depolarizing Potentials (GDPs); and that (iii) NKCC1 antagonist bumetanide suppresses GDPs and the excitatory actions of isoguvacine. In the hippocampal slices at P2-5, isoguvacine and synaptic activation of GABA(A)- Rs evoked excitatory responses at all slice depths, including surface and core. Thus, GABA exerts excitatory actions in the intact hippocampus (P1-3) and at all depths of hippocampal slices (P2-5). Therefore, the excitatory actions of GABA in hippocampal slices during the first postnatal days are not due to neuronal injury during slice preparation, and the trauma-related excitatory GABA actions at the slice surface are a fundamentally different phenomenon observed during the second postnatal week. © 2013 Valeeva, Valiullina and Khazipov

Stimulation Pattern-Dependent Plasticity at Hippocampal CCK-Positive Interneuron to Pyramidal Cell Perisomatic Inhibitory Synapses

© 2016, Springer Science+Business Media New York.Long-term plasticity plays an important role in the functional construction of neuronal networks. While anatomical wiring provides essential hardware for brain function, activity-dependent plasticity works as an adjustable software interface allowing sensory induced modification of transmission efficacy at given synaptic connections. In contrast to the vast majority of excitatory synapses, at distinct types of inhibitory GABAergic connections, the link between the pattern of activity and the subsequent change of synaptic strength has not been well characterized. Here, we examined frequency and stimulation pattern dependence in long-term synaptic depression at CCK+/CB1R inhibitory perisomatic synapses in the hippocampal CA1 region, and we found that successful LTD induction depends on the pattern of stimulation rather than the number of stimuli

Mechanisms of long-term plasticity of hippocampal GABAergic synapses

© 2017, Pleiades Publishing, Ltd.Long-term potentiation and depression of synaptic transmission have been considered as cellular mechanisms of memory in studies conducted in recent decades. These studies were predominantly focused on mechanisms underlying plasticity at excitatory synapses. Nevertheless, normal central nervous system functioning requires maintenance of a balance between inhibition and excitation, suggesting existence of similar modulation of glutamatergic and GABAergic synapses. Here we review the involvement of G-protein-coupled receptors in the generation of long-term changes in synaptic transmission of inhibitory synapses. We considered the role of endocannabinoid and glutamate systems, GABAB and opioid receptors in the induction of long-term potentiation and long-term depression in inhibitory synapses. The preand postsynaptic effects of activation of these receptors are also discussed

Selective Extracellular Stimulation of Pharmacologically Distinct CCK/CB1R Positive Interneuron to Pyramidal Cell Perisomatic Inhibitory Synapses

© 2016, Springer Science+Business Media New York.During prolonged whole cell recording, the intracellular contents are progressively dialyzed with the pipette solution; this often leads to significant changes in synaptic efficacy. To overcome this problem, we developed an approach allowing reliable extracellular stimulation of perisomatic synapses formed by CCK+/CB1+ interneurons onto CA1 pyramidal cells. Functional identification of this input was based on the unique features of CCK+/CB1+ terminals: long-lasting asynchronous transmitter release following high-frequency stimulation and exclusive expression of CB1R. Asynchronous release was used as an indication of proper positioning of the theta glass stimulation pipettes. We found that all extracellularly stimulated inputs with characteristic asynchronous release undergo robust DSI in response to 5-s depolarization and could also be almost entirely blocked by application of the CB1R agonist CP55940, which were similar to the data obtained with paired recordings from connected CB1+ and CA1 pyramidal cells. Thus, we have developed an approach allowing the selective and reliable extracellular stimulation of a subtype of hippocampal perisomatic inhibitory synapses

GABABR-dependent long-term depression at hippocampal synapses between CB1-positive interneurons and CA1 pyramidal cells

© 2016 Jappy, Valiullina, Draguhn and Rozov. Activity induced long lasting modifications of synaptic efficacy have been extensively studied in excitatory synapses, however, long term plasticity is also a property of inhibitory synapses. Inhibitory neurons in the hippocampal CA1 region can be subdivided according to the compartment they target on the pyramidal cell. Some interneurons preferentially innervate the perisomatic area and axon hillock of the pyramidal cells while others preferentially target dendritic branches and spines. Another characteristic feature allowing functional classification of interneurons is cell type specific expression of different neurochemical markers and receptors. In the hippocampal CA1 region, nearly 90% of the interneurons expressing cannabinoid type 1 receptors (CB1R) also express cholecystokinin (CCK). Therefore, the functional presence of CB1 receptors can be used for identification of the inhibitory input from CCK positive (CCK+) interneurons to CA1 pyramidal cells. The goal of this study was to explore the nature of long term plasticity at the synapses between interneurons expressing CB1 Rs (putative CCK+) and pyramidal neurons in the CA1 region of the hippocampus in vitro. We found that theta burst stimulation triggered robust long-term depression (LTD) at this synapse. The locus of LTD induction was postsynaptic and required activation of GABAb receptors. We also showed that LTD at this synaptic connection involves GABAbR- dependent suppression of adenylyl cyclase and consequent reduction of PKA activity. In this respect. CB1+ to pyramidal cell synapses differ from the majority of the other hippocampal inhibitory connections where theta burst stimulation results in long-term potentiation

The role of polyamine-dependent facilitation of calcium permeable ampars in short-term synaptic enhancement

© 2018 Rozov, Zakharova, Vazetdinova and Valiullina-Rakhmatullina. Depending on subunit composition AMPA receptor channels can be subdivided into two groups: GluA2-containing calcium impermeable AMPARs, and GluA2-lacking calcium permeable, AMPARs. These two groups differ in a number of biophysical properties and, most likely, in their functional role at glutamatergic synapses. GluA2-lacking channels have received a lot of attention over the last two decades mainly due to high calcium permeability, which was suggested to play a significant role in the induction of long-term synaptic plasticity in healthy tissue and neuronal death under neuropathological conditions. However, calcium permeable AMPARs possess another property that can contribute substantially to frequency dependent dynamics of synaptic efficacy. In the closed state calcium permeable AMPARs are blocked by endogenous polyamines, however, repetitive activation leads to progressive relief from the block and to the facilitation of ion flux through these channels. Polyamine-dependent facilitation of AMPARs can contribute to short-term plasticity at synapses that have high initial release probability and express calcium permeable AMPARs. During synaptic transmission activity-dependent relief from polyamine block of postsynaptic calcium-permeable AMPARs either counteracts presynaptic short-term depression in a frequency-dependent manner or, under specific stimulation conditions, induces facilitation of a synaptic response. Taking into account the fact that expression of calcium permeable AMPARs is developmentally regulated, depends on network activity and increases in diseased brain states, polyamine-dependent facilitation of calcium permeable AMPARs is an important, entirely postsynaptic mechanism of synaptic gain regulation

Resting membrane potential of the rat ventroposteriomedial thalamic neurons during postnatal development

Resting membrane potential is a critical parameter determining tonic or bursting mode of the thalamic neurons function. Previous developmental studies using whole-cell recordings revealed strongly depolarized values ofthe resting membrane potential (near -50 mV) in the immature VPM and LGN thalamic neurons. Yet, whole-cell recordings are associated with an introduction of the shunting conductance via the gigaseal that may lead to neuronal depolarization in small neurons with high, in the gigaohm range, membrane resistance. Therefore, we have performed measurements of the resting potential of VPM neurons in slices obtained from neonatal rats of postnatal days P2-P7 using cell-attached recordings of NMDA channels as voltage sensors. Because the currents through NM DA channels reverse near 0 mV, we assumed that the resting membrane potential should equal the reversal potential of currents through NMDA channels in cell-attached recordings. Analysis of the current-voltage relationships of NMDA currents revealed that the resting membrane potential in the immature VPM neurons is around -74 mV and that it does not change during the first postnatal week. This suggests that VPM neurons may operate in the bursting mode during the early postnatal period and support the oscillatory activity (spindle-like bursts) in the developing thalamocortical networks

GABA<inf>B</inf>R-dependent long-term depression at hippocampal synapses between CB1-positive interneurons and CA1 pyramidal cells

© 2016 Jappy, Valiullina, Draguhn and Rozov.Activity induced long lasting modifications of synaptic efficacy have been extensively studied in excitatory synapses, however, long term plasticity is also a property of inhibitory synapses. Inhibitory neurons in the hippocampal CA1 region can be subdivided according to the compartment they target on the pyramidal cell. Some interneurons preferentially innervate the perisomatic area and axon hillock of the pyramidal cells while others preferentially target dendritic branches and spines. Another characteristic feature allowing functional classification of interneurons is cell type specific expression of different neurochemical markers and receptors. In the hippocampal CA1 region, nearly 90% of the interneurons expressing cannabinoid type 1 receptors (CB1R) also express cholecystokinin (CCK). Therefore, the functional presence of CB1 receptors can be used for identification of the inhibitory input from CCK positive (CCK+) interneurons to CA1 pyramidal cells. The goal of this study was to explore the nature of long term plasticity at the synapses between interneurons expressing CB1 Rs (putative CCK+) and pyramidal neurons in the CA1 region of the hippocampus in vitro. We found that theta burst stimulation triggered robust long-term depression (LTD) at this synapse. The locus of LTD induction was postsynaptic and required activation of GABAb receptors. We also showed that LTD at this synaptic connection involves GABAbR- dependent suppression of adenylyl cyclase and consequent reduction of PKA activity. In this respect. CB1+ to pyramidal cell synapses differ from the majority of the other hippocampal inhibitory connections where theta burst stimulation results in long-term potentiation

The relative contribution of nmdars to excitatory postsynaptic currents is controlled by ca²⁺-induced inactivation

© 2016 Valiullina, Zakharova, Mukhtarov, Draguhn, Burnashev and Rozov.NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic excitation in several central neuronal networks. Therefore, we studied NMDAR-mediated synaptic currents in mouse hippocampal CA1 pyramidal neurons. Postsynaptic responses to subthreshold Schaffer collateral stimulation depended strongly on the absence or presence of intracellular Ca2+ buffers. Loading of pyramidal cells with exogenous Ca2+ buffers increased the amplitude and decay time of NMDAR mediated EPSCs (EPSPs) and prolonged the time window for action potential (AP) generation. Our data indicate that the Ca2+ influx mediated by unitary synaptic events is sufficient to produce detectable self-inhibition of NMDARs even at a physiological Mg2+ concentration. Therefore, the contribution of NMDARs to synaptic excitation is strongly controlled by both previous synaptic activity as well as by the Ca2+ buffer capacity of postsynaptic neurons

Layer specific development of neocortical pyramidal to fast spiking cell synapses

© 2016 Voinova, Valiullina, Zakharova, Mukhtarov, Draguhn and Rozov. All cortical neurons are engaged in inhibitory feedback loops which ensure excitation-inhibition balance and are key elements for the development of coherent network activity. The resulting network patterns are strongly dependent on the strength and dynamic properties of these excitatory-inhibitory loops which show pronounced regional and developmental diversity. Therefore we compared the properties and postnatal maturation of two different synapses between rat neocortical pyramidal cells (layer 2/3 and layer 5, respectively) and fast spiking (FS) intemeurons in the corresponding layer. At P14, both synapses showed synaptic depression upon repetitive activation. Synaptic release properties between layer 2/3 pyramidal cells and FS cells were stable from P14 to P28. In contrast, layer 5 pyramidal to FS cell connections showed a significant increase in paired pulse ratio by P28. Presynaptic calcium dynamics also changed at these synapses, including sensitivity to exogenously loaded calcium buffers and expression of presynaptic calcium channel subtypes. These results underline the large variety of properties at different, yet similar, synapses in the neocortex. They also suggest that postnatal maturation of the brain goes along with increasing differences between synaptically driven network activity in layer 5 and layer 2/3