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In central neurons, information flows from the dendritic surface toward the axon terminals. We found that during in vitro gamma oscillations, ectopic action potentials are generated at high frequency in the distal axon of pyramidal cells (PCs) but do not invade the soma. At the same time, axo-axonic cells (AACs) discharged at a high rate and tonically inhibited the axon initial segment, which can be instrumental in preventing ectopic action potential back-propagation. We found that activation of a single AAC substantially lowered soma invasion by antidromic action potential in postsynaptic PCs. In contrast, activation of soma-inhibiting basket cells had no significant impact. These results demonstrate that AACs can separate axonal from somatic activity and maintain the functional polarization of cortical PCs during network oscillations.

Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner. Changes in the strength of synapses – the connections between neurons – form the basis of learning and memory. This process, which is known as synaptic plasticity, incorporates transient experiences into persistent memory traces. However, a single synapse should not be viewed in isolation. Neurons typically belong to extensive networks made up of large numbers of cells, which show coordinated patterns of activity. The synchronized firing of the neurons in such a network is referred to as a network oscillation. The frequency of an oscillation – that is, the number of times per second that its component cells are active at the same time – reflects distinct physiological functions. For example, high frequency oscillations called gamma waves help new memories to form, but it is not clear exactly how they do this. By studying gamma oscillations in a brain region called the hippocampus, Zarnadze, Bäuerle et al. provide insights into the underlying mechanisms. Signals from “excitatory” neurons make the neuron on the other side of the synapse more likely to fire in response, and signals for “inhibitory” neurons make it less likely to fire. By recording the activity of excitatory neurons in mouse brain slices, Zarnadze, Bäuerle et al. show that gamma oscillations increase the strength of excitatory synapses in the hippocampus, allowing neurons to signal more easily across these connections. Blocking the activity of a protein called metabotropic glutamate receptor 5 prevents this increase in excitatory synaptic strength, suggesting that these receptors play an important role in memory processing. In contrast to excitatory neurons, gamma oscillations have different effects on two types of inhibitory neurons within the hippocampus. The oscillations increase the excitability of gamma-supporting inhibitory neurons, but at the same time reduce that of gamma-disturbing inhibitory neurons. These opposing changes in turn support synaptic plasticity. By showing that gamma oscillations contribute to changes in synaptic strength within the hippocampus, Zarnadze, Bäuerle et al. help to explain the importance of these rhythms for memory processing. Further research is now needed to fully decipher the roles of different cell types, and the synaptic connections between them, in the formation of new memories.

The hippocampal output structure, the subiculum, expresses two major memory relevant network rhythms, sharp wave ripple and gamma frequency oscillations. To this date, it remains unclear how the two distinct types of subicular principal cells, intrinsically bursting and regular spiking neurons, participate in these two network rhythms. Using concomitant local field potential and intracellular recordings in an in vitro mouse model that allows the investigation of both network rhythms, we found a cell type-specific segregation of principal neurons into participating intrinsically bursting and non-participating regular spiking cells. However, if regular spiking cells were kept at a more depolarized level, they did participate in a specific manner, suggesting a potential bimodal working model dependent on the level of excitation. Furthermore, intrinsically bursting and regular spiking cells exhibited divergent intrinsic membrane and synaptic properties in the active network. Thus, our results suggest a cell-type-specific segregation of principal cells into two separate groups during network activities, supporting the idea of two parallel streams of information processing within the subiculum.

GABA B receptors (GABA BRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA BR agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK ⁺ BCs), through enhanced inhibition of GABA release via presynaptic GABA BRs. We conclude that cell type–specific up-regulation of GABA BR-mediated autoinhibition in CCK ⁺ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.

Gamma frequency (30-80 Hz) network oscillations have been observed in the hippocampus during several behavioral paradigms in which they are often modulated by a theta frequency (4-12 Hz) oscillation. Interneurons of the hippocampus have been shown to be crucially involved in rhythms generation, and several subtypes with distinct anatomy and physiology have been described. In particular, the oriens lacunosum-moleculare (O-LM) interneurons were shown to synapse on distal apical dendrites of pyramidal cells and to spike preferentially at theta frequency, even in the presence of gamma-field oscillations. O-LM cells have also recently been shown to present higher axonal ramification in the longitudinal axis of the hippocampus. By using a hippocampal network model composed of pyramidal cells and two types of interneurons (O-LM and basket cells), we show here that the O-LM interneurons lead to gamma coherence between anatomically distinct cell modules. We thus propose that this could be a mechanism for coupling longitudinally distant cells excited by entorhinal cortex inputs into gamma-coherent assemblies.

Synaptic transmission relies on effective and accurate compensatory endocytosis. F‐BAR proteins may serve as membrane curvature sensors and/or inducers and thereby support membrane remodelling processes; yet, their in vivo functions urgently await disclosure. We demonstrate that the F‐BAR protein syndapin I is crucial for proper brain function. Syndapin I knockout (KO) mice suffer from seizures, a phenotype consistent with excessive hippocampal network activity. Loss of syndapin I causes defects in presynaptic membrane trafficking processes, which are especially evident under high‐capacity retrieval conditions, accumulation of endocytic intermediates, loss of synaptic vesicle (SV) size control, impaired activity‐dependent SV retrieval and defective synaptic activity. Detailed molecular analyses demonstrate that syndapin I plays an important role in the recruitment of all dynamin isoforms, central players in vesicle fission reactions, to the membrane. Consistently, syndapin I KO mice share phenotypes with dynamin I KO mice, whereas their seizure phenotype is very reminiscent of fitful mice expressing a mutant dynamin. Thus, syndapin I acts as pivotal membrane anchoring factor for dynamins during regeneration of SVs. F‐BAR domain proteins sense or induce membrane curvature and play a widespread role in intracellular trafficking events. This study characterizes syndapin I knockout mice at the neurological, cell biological and molecular levels and demonstrates that this F‐BAR protein acts as membrane anchoring factor for dynamins during synaptic vesicle regeneration.

As a structure involved in learning and memory, the hippocampus functions as a network. The functional differentiation along the longitudinal axis of the hippocampus is poorly demarcated in comparison with the transverse axis. Using patch clamp recordings in conjunction with post hoc anatomy, we have examined the pattern of connectivity and the functional differentiation along the long axis of the hippocampus. Here, we provide anatomical and physiological evidence that the prominent rhythmic network activities of the hippocampus, the behavior-specific gamma and theta oscillations, are seen predominantly along the transverse and longitudinal axes respectively. This orthogonal relationship is the result of the axonal field trajectories and the consequential interaction of the principal cells and major interneuron subtypes involved in generating each rhythm. Thus, the axonal arborization patterns of hippocampal inhibitory cells may represent a structural framework for the spatiotemporal distribution of activity observed within the hippocampus.

Mesial temporal lobe epilepsy (mTLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. Injection of kainic acid (KA) into the dorsal hippocampus of mice reproduces major electrophysiological and histopathological characteristics of mTLE. In extracellular recordings from the morphologically intact ventral hippocampus of KA-injected epileptic mice, we found that theta-frequency oscillations were abolished, whereas gamma oscillations persisted both in vivo and in vitro. Whole-cell recordings further showed that oriens-lacunosum-moleculare (O-LM) interneurons, key players in the generation of theta rhythm, displayed marked changes in their intrinsic and synaptic properties. Hyperpolarization-activated mixed cation currents (Ih) were significantly reduced, resulting in an increase in the input resistance and a hyperpolarizing shift in the resting membrane potential. Additionally, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was increased, indicating a stronger excitatory input to these neurons. As a consequence, O-LM interneurons increased their firing rate from theta to gamma frequencies during induced network activity in acute slices from KA-injected mice. Thus, our physiological data together with network simulations suggest that changes in excitatory input and synaptic integration in O-LM interneurons lead to impaired rhythmogenesis in the hippocampus that in turn may underlie memory deficit.

The medial entorhinal cortex (mEC) plays a critical role for spatial navigation and memory. While many studies have investigated the principal neurons within the entorhinal cortex, much less is known about the inhibitory circuitries within this structure. Here, we describe for the first time in the mEC a subset of parvalbumin-positive (PV+) interneurons (INs)—stuttering cells (STUT)—with morphological, intrinsic electrophysiological, and synaptic properties distinct from fast-spiking PV+ INs. In contrast to the fast-spiking PV+ INs, the axon of the STUT INs also terminated in layer 3 and showed subthreshold membrane oscillations at gamma frequencies. Whereas the synaptic output of the STUT INs was only weakly reduced by a μ-opioid agonist, their inhibitory inputs were strongly suppressed. Given these properties, STUT are ideally suited to entrain gamma activity in the pyramidal cell population of the mEC. We propose that activation of the μ-opioid receptors decreases the GABA release from the PV+ INs onto the STUT, resulting in disinhibition of the STUT cell population and the consequent increase in network gamma power. We therefore suggest that the opioid system plays a critical role, mediated by STUT INs, in the neural signaling and oscillatory network activity within the mEC.

In patients with drug-resistant epilepsy, surgical resection of the seizure focus may represent the best treatment option. In Georgia, a structured epilepsy surgery program was lacking until 2017, when a German-Georgian project was initiated to establish necessary facilities, define diagnostic and treatment standards, and educate local healthcare providers. After a scientific symposium in Tbilisi in 2017, six surgical intervention visits have taken place. Georgian epileptologists and a neuropsychologist visited the Berlin-Brandenburg Epilepsy Center to observe presurgical evaluation procedures. Surgical indications are made by the Georgian team and discussed with German epileptologists either in Tbilisi or via online conferences. Scientific and educational efforts have been launched to address drug-resistant epilepsy topics more broadly. Since 2018, 13 patients with temporal lobe epilepsy and hippocampal sclerosis have undergone resective epilepsy surgery. In September 2023, seven patients with 12+ months follow-up were examined. Five patients became completely seizure-free (ILAE 1), one had auras (ILAE 2), and one had disabling seizures (ILAE 4). Quality of life improved substantially, and antiseizure medication was reduced in many cases. Most patients reported better memory function and returned to work. All except one patient rated their surgery decision as “good”. Supporting complex medical procedures in regions in need can be rewarding but must meet specialized standards. The seizure outcomes in Georgia compare favorably with existing literature, showing that careful education and teamwork can achieve excellent results despite technical limitations. The teams have become close collaborators, and efforts continue to provide high-quality epilepsy surgery for the Georgian population. Bei Patienten mit therapieresistenter Epilepsie kann die chirurgische Resektion des Anfallsherds die beste Behandlungsoption darstellen. In Georgien fehlte bis 2017 ein strukturiertes Epilepsiechirurgie-Programm. Dann wurde ein deutsch-georgisches Projekt initiiert, um die notwendigen Einrichtungen aufzubauen, diagnostische und therapeutische Standards zu definieren und lokale Gesundheitsdienstleister auszubilden. Nach einem wissenschaftlichen Symposium in Tiflis 2017 fanden sechs chirurgische Interventionsbesuche statt. Georgische Epileptologen und ein Neuropsychologe besuchten das Berlin-Brandenburger Epilepsie-Zentrum, um die prächirurgischen Evaluationsverfahren kennenzulernen. Die Operationsindikationen werden vom georgischen Team gestellt und mit deutschen Epileptologen entweder in Tiflis oder per Online-Konferenz besprochen. Wissenschaftliche und bildungspolitische Initiativen wurden gestartet, um Themen der therapieresistenten Epilepsie umfassender zu behandeln. Seit 2018 wurden 13 Patienten mit Temporallappenepilepsie und Hippokampussklerose epilepsiechirurgisch behandelt. Im September 2023 wurden sieben Patienten mit einer Nachbeobachtungszeit von mindestens 12 Monaten untersucht. Fünf Patienten wurden komplett anfallsfrei (ILAE 1), einer hatte noch Auren (ILAE 2) und einer weiterhin behindernde Anfälle (ILAE 4). Die Lebensqualität verbesserte sich erheblich, und die antiepileptische Medikation konnte in vielen Fällen reduziert werden. Die meisten Patienten berichteten über eine verbesserte Gedächtnisfunktion und kehrten zur Arbeit zurück. Alle bis auf einen Patienten bewerteten ihre Operationsentscheidung rückblickend als „gut“. Die Unterstützung komplexer medizinischer Verfahren in bedürftigen Regionen kann zwar lohnend sein, muss aber spezialisierte Standards erfüllen. Die Anfallsergebnisse in Georgien sind im Vergleich zur bestehenden Literatur positiv, was zeigt, dass sorgfältige Ausbildung und Teamarbeit trotz technischer Einschränkungen zu hervorragenden Ergebnissen führen können. Die Teams sind zu engen Mitarbeitern geworden, und die Bemühungen, der georgischen Bevölkerung qualitativ hochwertige Epilepsiechirurgie anzubieten, werden fortgesetzt.