Lisa Topolnik

Hyperexcitability of intact neurons underlies acute development of trauma-related electrographic seizures in cats in vivo.

Cortical trauma can lead to development of electrographic paroxysmal activities. Current views of trauma‐induced epileptogenesis suggest that chronic neuronal hyperexcitability and extensive morphological reorganization of the traumatized cortex are required for the generation of electrographic seizures. However, the mechanisms responsible for the initiation of electrographic seizures shortly after cortical injury are poorly understood. Here we show that, in the experimental model of partially deafferented (undercut) cortex, an increase in intrinsic and synaptic excitability of neurons in areas adjacent to the undercut cortex is sufficient for the generation of electrographic paroxysmal activity within few hours after partial cortical deafferentation. Locally increased and spatially restricted neuronal excitability arose from the increased incidence of intrinsically bursting neurons, enhanced intrinsic and synaptic neuronal responsiveness, and slight disinhibition. These mechanisms only operate in neurons located in the vicinity of partially deafferented sites because, after the cortical injury, partially deafferented neurons are mostly silent and hypoexcitable. Our results suggest that trauma‐induced electrographic seizures first arise in cortical fields that are closest to the site of injury and such seizures do not require long‐term neuronal reorganization.

Differential regulation of metabotropic glutamate receptor- and AMPA receptor-mediated dendritic Ca2+ signals by presynaptic and postsynaptic activity in hippocampal interneurons.

Calcium plays a crucial role as a ubiquitous second messenger and has a key influence in many forms of synaptic plasticity in neurons. The spatiotemporal properties of dendritic Ca2+ signals in hippocampal interneurons are relatively unexplored. Here we use two-photon calcium imaging and whole-cell recordings to study properties of dendritic Ca2+ signals mediated by different glutamate receptors and their regulation by synaptic activity in oriens/alveus (O/A) interneurons of rat hippocampus. We demonstrate that O/A interneurons express Ca2+-permeable AMPA receptors (CP-AMPARs) providing fast Ca2+ signals. O/A cells can also coexpress CP-AMPARs, Ca2+-impermeable AMPARs (CI-AMPARs), and group I/II metabotropic glutamate receptors (mGluRs) (including mGluR1a), in the same cell. CI-AMPARs are often associated with mGluRs, resulting in longer-lasting Ca2+ signals than CP-AMPAR-mediated responses. Finally, CP-AMPAR- and mGluR-mediated Ca2+ signals demonstrate distinct voltage dependence and are differentially regulated by presynaptic and postsynaptic activity: weak synaptic stimulation produces Ca2+ signals mediated by CP-AMPARs, whereas stronger stimulation, or weak stimulation coupled with postsynaptic depolarization, recruits Ca2+ signals mediated by mGluRs. Our results suggest that differential activation of specific glutamate receptor-mediated Ca2+ signals within spatially restricted dendritic microdomains may serve distinct signaling functions and endow oriens/alveus interneurons with multiple forms of Ca2+-mediated synaptic plasticity. Specific activation of mGluR-mediated Ca2+ signals by coincident presynaptic and postsynaptic activity fulfills the conditions for Hebbian pairing and likely underlies their important role in long-term potentiation induction at O/A interneuron synapses.

Staufen1 Regulation of Protein Synthesis-Dependent Long-Term Potentiation and Synaptic Function in Hippocampal Pyramidal Cells

ABSTRACT Staufen1 (Stau1) is an RNA-binding protein involved in transport, localization, decay, and translational control of mRNA. In neurons, it is present in cell bodies and also in RNA granules which are transported along dendrites. Dendritic mRNA localization might be involved in long-term synaptic plasticity and memory. To determine the role of Stau1 in synaptic function, we examined the effects of Stau1 down-regulation in hippocampal slice cultures using small interfering RNA (siRNA). Biolistic transfection of Stau1 siRNA resulted in selective down-regulation of Stau1 in slice cultures. Consistent with a role of Stau1 in transporting mRNAs required for synaptic plasticity, Stau1 down-regulation impaired the late form of chemically induced long-term potentiation (L-LTP) without affecting early-LTP, mGluR1/5-mediated long-term depression, or basal evoked synaptic transmission. Stau1 down-regulation decreased the amplitude and frequency of miniature excitatory postsynaptic currents, suggesting a role in maintaining efficacy at hippocampal synapses. At the cellular level, Stau1 down-regulation shifted spine shape from regular to elongated spines, without changes in spine density. The change in spine shape could be rescued by an RNA interference-resistant Stau1 isoform. Therefore, Stau1 is important for processing and/or transporting in dendrites mRNAs that are critical in regulation of synaptic strength and maintenance of functional connectivity changes underlying hippocampus-dependent learning and memory.

Activity-Dependent Compartmentalized Regulation of Dendritic Ca2+ Signaling in Hippocampal Interneurons

Activity-dependent regulation of synaptic inputs in neurons is controlled by highly compartmentalized and dynamic dendritic calcium signaling. Among multiple Ca2+ mechanisms operating in neuronal dendrites, voltage-sensitive Ca2+ channels (VSCCs) represent a major source of Ca2+ influx; however, their use-dependent implication, regulation, and function in different types of central neurons remain widely unknown. Using two-photon microscopy to probe Ca2+ signaling in dendrites of hippocampal oriens/alveus interneurons, we found that intense synaptic activity or local activation of mGluR5 induced long-lasting potentiation of action potential evoked Ca2+ transients. This potentiation of dendritic Ca2+ signaling required mGluR5-induced intracellular Ca2+ release and PKC activation and was expressed as a selective compartmentalized potentiation of L-type VSCCs. Thus, in addition to mGluR1a-dependent synaptic plasticity, hippocampal interneurons in the feedback inhibitory circuit demonstrate a novel form of mGluR5-induced dendritic plasticity. Given an implication of L-type VSCCs in the induction of Hebbian LTP at interneuron excitatory synapses, their activity-dependent regulation may represent a powerful mechanism for regulating synaptic plasticity.

Synapse-Specific Inhibitory Control of Hippocampal Feedback Inhibitory Circuit

Local circuit and long-range GABAergic projections provide powerful inhibitory control over the operation of hippocampal inhibitory circuits, yet little is known about the input- and target-specific organization of interacting inhibitory networks in relation to their specific functions. Using a combination of two-photon laser scanning photostimulation and whole-cell patch clamp recordings in mice hippocampal slices, we examined the properties of transmission at GABAergic synapses formed onto hippocampal CA1 stratum oriens – lacunosum moleculare (O–LM) interneurons by two major inhibitory inputs: local projection originating from stratum radiatum interneurons and septohippocampal GABAergic terminals. Optical mapping of local inhibitory inputs to O–LM interneurons revealed that vasoactive intestinal polypeptide- and calretinin-positive neurons, with anatomical properties typical of type III interneuron-specific interneurons, provided the major local source of inhibition to O–LM cells. Inhibitory postsynaptic currents evoked by minimal stimulation of this input exhibited small amplitude and significant paired-pulse and multiple-pulse depression during repetitive activity. Moreover, these synapses failed to show any form of long-term synaptic plasticity. In contrast, synapses formed by septohippocampal projection produced higher amplitude and persistent inhibition and exhibited long-term potentiation induced by theta-like activity. These results indicate the input and target-specific segregation in inhibitory control, exerted by two types of GABAergic projections and responsible for distinct dynamics of inhibition in O–LM interneurons. The two inputs are therefore likely to support the differential activity- and brain state-dependent recruitment of hippocampal feedback inhibitory circuits in vivo, crucial for dendritic disinhibition and computations in CA1 pyramidal cells.

Cell type‐specific and activity‐dependent dynamics of action potential‐evoked Ca2+ signals in dendrites of hippocampal inhibitory interneurons

Non‐technical summary  Action potentials generated at the level of the cell body can propagate back to neuronal dendrites, where they activate different types of voltage‐sensitive calcium channels and produce massive calcium influx. Although these calcium signals may control dendritic integration, their mechanisms, dynamic properties and role in different cell types remain largely unknown. We found that in dendrites of hippocampal interneurons, an inhibitory cell type involved in control of network excitability, specific types of calcium channels are present but are recruited in an activity‐dependent manner. Furthermore, their activation produces calcium rises spatially restricted to proximal dendritic sites, where they control the efficacy of transmission at inhibitory synapses. The pathway by which this happens appears to constitute a negative feedback loop – increased firing activity of interneurons potentiates the inhibitory drive that they receive, thus decreasing the activity of interneurons further. This may have a profound effect on the recruitment of interneurons and network activity.

Age-dependent remodelling of inhibitory synapses onto hippocampal CA1 oriens-lacunosum moleculare interneurons

Non‐Technical Summary  The main function of the inhibitory synapse is to provide the membrane hyperpolarization and, thereby, to control the level of activity of its target cell. Extensively studied in pyramidal neurons, the properties of inhibitory synapses that target inhibitory interneurons remain largely unknown. We studied the properties of inhibitory synapses formed onto interneurons involved in the hippocampal feedback inhibitory circuit. Our data revealed a significant, age‐dependent strengthening of inhibition of interneurons due to the synaptic incorporation of the α5 subunit of the GABAA receptor. This novel mechanism of age‐dependent refinement of local circuit inhibition may have a direct impact on the hippocampal network activity and performance during development.

Coordination of dendritic inhibition through local disinhibitory circuits

It has been recognized for some time that different subtypes of cortical inhibitory interneurons innervate specific dendritic domains of principal cells and release GABA at particular times during behaviorally relevant network oscillations. However, the lack of basic information on how the activity of interneurons can be controlled by GABA released in particular behavioral states has hindered our understanding of the rules that govern the spatio-temporal organization and function of dendritic inhibition. Similar to principal cells, any given interneuron may receive several functionally distinct inhibitory inputs that target its specific subcellular domains. We recently found that local circuitry of the so-called interneuron-specific (IS) interneurons is responsible for dendritic inhibition of different subtypes of hippocampal interneurons with a great impact on cell output. Here, we will review the properties and the specificity of connections of IS interneurons in the CA1 hippocampus and neocortex, and discuss their possible role in the activity-dependent regulation of dendritic inhibition received by pyramidal neurons.

Dendritic Signaling in Inhibitory Interneurons: Local Tuning via Group I Metabotropic Glutamate Receptors

Communication between neurons is achieved by rapid signal transduction via highly specialized structural elements known as synaptic contacts. In addition, numerous extrasynaptic mechanisms provide a flexible platform for the local regulation of synaptic signals. For example, peri- and extra-synaptic signaling through the group I metabotropic glutamate receptors (mGluRs) can be involved in the highly compartmentalized regulation of dendritic ion conductances, the induction of input-specific synaptic plasticity, and the local release of retrograde messengers. Therefore, extrasynaptic mechanisms appear to play a key role in the local tuning of dendritic computations. Here, we review recent findings on the role of group I mGluRs in the dendritic signaling of inhibitory interneurons. We propose that group I mGluRs provide a dual-mode signaling device that integrates different patterns of neural activity. By implementing distinct forms of intrinsic and synaptic regulation, group I mGluRs may be responsible for the local fine-tuning of dendritic function.

Non-linear calcium signalling and synaptic plasticity in interneurons

Understanding of how intracellular calcium (Ca2+) signals regulate the efficacy of transmission at excitatory and inhibitory synapses in the central nervous system (CNS) has been a focus of intense investigation. This review discusses recent findings on how Ca2+ signals are integrated in dendrites of inhibitory interneurons to regulate their synapses. In particular, Ca2+ signaling through intracellular Ca2+ release plays an essential role in synaptic signal transduction and experience-dependent plasticity in dendrites of interneurons. Understanding the alternative pathways of Ca2+ signaling in the absence of canonical voltage-gated Ca2+ mechanisms is beginning to shed light on how their regulation can contribute to interneuron function and dysfunction in disease.