Increased Interhemispheric Connectivity of a Distinct Type of Hippocampal Pyramidal Cells.

Neurons typically generate action potentials at their axon initial segment based on the integration of synaptic inputs. In many neurons, the axon extends from the soma, equally weighting dendritic inputs. A notable exception is found in a subset of hippocampal pyramidal cells where the axon emerges from a basal dendrite. This structure allows these axon-carrying dendrites (AcDs) a privileged input route. We found that in male mice, such cells in the CA1 region receive stronger excitatory input from the contralateral CA3, compared with those with somatic axon origins. This is supported by a higher count of putative synapses from contralateral CA3 on the AcD. These findings, combined with prior observations of their distinct role in sharp-wave ripple firing, suggest a key role of this neuron subset in coordinating bi-hemispheric hippocampal activity during memory-centric oscillations.

Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice.

Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. However, it remains unknown whether IEG expression may play a role in memory suppression. Here we uncovered a novel function of the IEG neuronal PAS domain protein 4 (Npas4), as an inducible memory suppressor gene of highly salient aversive experiences. Using a contextual fear conditioning paradigm, we found that low stimulus salience leads to monophasic Npas4 expression, while highly salient learning induces a biphasic expression of Npas4 in the hippocampus. The later phase requires N-methyl-D-aspartate (NMDA) receptor activity and is independent of dopaminergic neurotransmission. Our in vivo pharmacological and genetic manipulation experiments suggested that the later phase of Npas4 expression restricts the consolidation of a fear memory and promote behavioral flexibility, by facilitating fear extinction and the contextual specificity of fear responses. Moreover, immunofluorescence and electrophysiological analysis revealed a concomitant increase in synaptic input from cholecystokinin (CCK)-expressing interneurons. Our results demonstrate how salient experiences evoke unique temporal patterns of IEG expression that fine-tune memory consolidation. Moreover, our study provides evidence for inducible gene expression associated with memory suppression as a possible mechanism to balance the consolidation of highly salient memories, and thereby to evade the formation of maladaptive behavior.

Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory.

Canonical transient receptor potential (TRPC) channels influence various neuronal functions. Using quantitative high-resolution mass spectrometry, we demonstrate that TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. In hippocampal neurons from Trpc1/Trpc4/Trpc5-triple-knockout (Trpc1/4/5-/-) mice, lacking any TRPC1-, TRPC4-, or TRPC5-containing channels, action potential-triggered excitatory postsynaptic currents (EPSCs) were significantly reduced, whereas frequency, amplitude, and kinetics of quantal miniature EPSC signaling remained unchanged. Likewise, evoked postsynaptic responses in hippocampal slice recordings and transient potentiation after tetanic stimulation were decreased. In vivo, Trpc1/4/5-/- mice displayed impaired cross-frequency coupling in hippocampal networks and deficits in spatial working memory, while spatial reference memory was unaltered. Trpc1/4/5-/- animals also exhibited deficiencies in adapting to a new challenge in a relearning task. Our results indicate the contribution of heteromultimeric channels from TRPC1, TRPC4, and TRPC5 subunits to the regulation of mechanisms underlying spatial working memory and flexible relearning by facilitating proper synaptic transmission in hippocampal neurons.

Synchronicity of excitatory inputs drives hippocampal networks to distinct oscillatory patterns.

The rodent hippocampus expresses a variety of neuronal network oscillations depending on the behavioral state of the animal. Locomotion and active exploration are accompanied by theta-nested gamma oscillations while resting states and slow-wave sleep are dominated by intermittent sharp wave-ripple complexes. It is believed that gamma rhythms create a framework for efficient acquisition of information whereas sharp wave-ripples are thought to be involved in consolidation and retrieval of memory. While not strictly mutually exclusive, one of the two patterns usually dominates in a given behavioral state. Here we explore how different input patterns induce either of the two network states, using an optogenetic stimulation approach in hippocampal brain slices of mice. We report that the pattern of the evoked oscillation depends strongly on the initial synchrony of activation of excitatory cells within CA3. Short, synchronous activation favors the emergence of sharp wave-ripple complexes while persistent but less synchronous activity-as typical for sensory input during exploratory behavior-supports the generation of gamma oscillations. This dichotomy is reflected by different degrees of synchrony of excitatory and inhibitory synaptic currents within these two states. Importantly, the induction of these two fundamental network patterns does not depend on the presence of any neuromodulatory transmitter like acetylcholine, but is merely based on a different synchrony in the initial activation pattern.

Amyloid Precursor Protein Protects Neuronal Network Function after Hypoxia via Control of Voltage-Gated Calcium Channels.

UNLABELLED: Acute cerebral ischemia and chronic neurovascular diseases share various common mechanisms with neurodegenerative diseases, such as disturbed cellular calcium and energy homeostasis and accumulation of toxic metabolites. A link between these conditions may be constituted by amyloid precursor protein (APP), which plays a pivotal role in the pathogenesis of Alzheimer's disease, but has also been associated with the response to acute hypoxia and regulation of calcium homeostasis. We therefore studied hypoxia-induced loss of function and recovery upon reoxygenation in hippocampal slices of mice lacking APP (APP(-/-)) or selectively expressing its soluble extracellular domain (APPsα-KI). Transient hypoxia disrupted electrical activity at the network and cellular level. In mice lacking APP, these impairments were significantly more severe, showing increased rise of intracellular calcium, faster loss of function, and higher incidence of spreading depression. Likewise, functional recovery upon reoxygenation was much slower and less complete than in controls. Most of these deficits were rescued by selective expression of the soluble extracellular fragment APPsα, or by pharmacological block of L-type calcium channels. We conclude that APP supports neuronal resistance toward acute hypoxia. This effect is mediated by the secreted APPsα-domain and involves L-type calcium channels. SIGNIFICANCE STATEMENT: Amyloid precursor protein (APP) is involved in the pathophysiology of Alzheimer's disease, but its normal function in the brain remains elusive. Here, we describe a neuroprotective role of the protein in acute hypoxia. Functional recovery of mouse hippocampal networks after transient reduction of oxygen supply was strongly impaired in animals lacking APP. Most protective effects are mediated by the soluble extracellular fragment APPsα and involve L-type calcium channels. Thus, APP contributes to calcium homeostasis in situations of metabolic stress. This finding may shed light on the physiological function of APP and may be important for understanding mechanisms of neurodegenerative diseases.

Downstream effects of hippocampal sharp wave ripple oscillations on medial entorhinal cortex layer V neurons in vitro.

The entorhinal cortex (EC) is a critical component of the medial temporal lobe (MTL) memory system. Local networks within the MTL express a variety of state-dependent network oscillations that are believed to organize neuronal activity during memory formation. The peculiar pattern of sharp wave-ripple complexes (SPW-R) entrains neurons by a very fast oscillation at ∼200 Hz in the hippocampal areas CA3 and CA1 and then propagates through the "output loop" into the EC. The precise mechanisms of SPW-R propagation and the resulting cellular input patterns in the mEC are, however, largely unknown. We therefore investigated the activity of layer V (LV) principal neurons of the medial EC (mEC) during SPW-R oscillations in horizontal mouse brain slices. Intracellular recordings in the mEC were combined with extracellular monitoring of propagating network activity. SPW-R in CA1 were regularly followed by negative field potential deflections in the mEC. Propagation of SPW-R activity from CA1 to the mEC was mostly monosynaptic and excitatory, such that synaptic input to mEC LV neurons directly reflected unit activity in CA1. Comparison with propagating network activity from CA3 to CA1 revealed a similar role of excitatory long-range connections for both regions. However, SPW-R-induced activity in CA1 involved strong recruitment of rhythmic synaptic inhibition and corresponding fast field oscillations, in contrast to the mEC. These differences between features of propagating SPW-R emphasize the differential processing of network activity by each local network of the hippocampal output loop. © 2016 Wiley Periodicals, Inc.

Differential effects of oxytocin on mouse hippocampal oscillations in vitro.

The hypothalamic neuropeptide oxytocin (OT) controls childbirth and lactation, is involved in social behaviors, plays a role in various psychiatric disorders, and has effects on learning and memory. Although behavioral effects of OT have been extensively studied, much less is known about its effects on neuronal and network activity patterns. Here, we investigate the effect of OT on two major patterns of hippocampal network activity in mouse hippocampal slices. We studied different in vitro models of gamma-frequency oscillations and sharp wave-ripple complexes (SPW-R), two patterns implicated in spatial memory formation and memory consolidation respectively. Strikingly, we found a profound difference of OT on these distinct, mutually exclusive activity patterns. While gamma oscillations where not affected by the activation of hippocampal OT receptors, SPW-R were potently and rapidly suppressed. Interestingly, the temporal precision of oscillation-coupled spikes was enhanced at the same time. Thus, OT exerts strongly different modulatory effects on different network patterns, most likely by inhibition of different sets of inhibitory interneurons. The observed dichotomy between gamma and SPW-R oscillations may have profound effects on the behavioral and cognitive effects of OT which are relevant to cognitive processes and to psychiatric diseases.

Optimized temporally deconvolved Ca²âº imaging allows identification of spatiotemporal activity patterns of CA1 hippocampal ensembles.

Hippocampal activity is characterized by the coordinated firing of a subset of neurons. Such neuronal ensembles can either be driven by external stimuli to form new memory traces or be reactivated by intrinsic mechanisms to reactivate and consolidate old memories. Hippocampal network oscillations orchestrate this coherent activity. One key question is how the topology, i.e. the functional connectivity of neuronal networks supports their desired function. Recently, this has been addressed by characterizing the intrinsic properties for the highly recurrently connected CA3 region using organotypic slice cultures and Ca(2+) imaging. In the present study, we aimed to determine the properties of CA1 hippocampal ensembles at high temporal and multiple single cell resolution. Thus, we performed Ca(2+) imaging using the chemical fluorescent Ca(2+) indicator Oregon Green BAPTA 1-AM. To achieve most physiological conditions, we used acute hippocampal slices that were recorded in a so-called interface chamber. To faithfully reconstruct firing patterns of multiple neurons in the field of view, we optimized deconvolution-based detection of action potential associated Ca(2+) events. Our approach outperformed currently available detection algorithms by its sensitivity and robustness. In combination with advanced network analysis, we found that acute hippocampal slices contain a median of 11 CA1 neuronal ensembles with a median size of 4 neurons. This apparently low number of neurons is likely due to the confocal imaging acquisition and therefore yields a lower limit. The distribution of ensemble sizes was compatible with a scale-free topology, as far as can be judged from data with small cell numbers. Interestingly, cells were more tightly clustered in large ensembles than in smaller groups. Together, our data show that spatiotemporal activity patterns of hippocampal neuronal ensembles can be reliably detected with deconvolution-based imaging techniques in mouse hippocampal slices. The here presented techniques are fully applicable to similar studies of distributed optical measurements of neuronal activity (in vivo), where signal-to-noise ratio is critical.

Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro.

The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal networks.

Cellular correlate of assembly formation in oscillating hippocampal networks in vitro.

Neurons form transiently stable assemblies that may underlie cognitive functions, including memory formation. In most brain regions, coherent activity is organized by network oscillations that involve sparse firing within a well-defined minority of cells. Despite extensive work on the underlying cellular mechanisms, a fundamental question remains unsolved: how are participating neurons distinguished from the majority of nonparticipators? We used physiological and modeling techniques to analyze neuronal activity in mouse hippocampal slices during spontaneously occurring high-frequency network oscillations. Network-entrained action potentials were exclusively observed in a defined subset of pyramidal cells, yielding a strict distinction between participating and nonparticipating neurons. These spikes had unique properties, because they were generated in the axon without prior depolarization of the soma. GABA(A) receptors had a dual role in pyramidal cell recruitment. First, the sparse occurrence of entrained spikes was accomplished by intense perisomatic inhibition. Second, antidromic spike generation was facilitated by tonic effects of GABA in remote axonal compartments. Ectopic spike generation together with strong somatodendritic inhibition may provide a cellular mechanism for the definition of oscillating assemblies.

Effects of the GABA-uptake blocker NNC-711 on spontaneous sharp wave-ripple complexes in mouse hippocampal slices.

The precise temporal and spatial activity patterns of neurons in cortical networks are organized by different state-dependent types of network oscillations. GABAergic inhibition plays a key role in the underlying mechanisms of such oscillations and it has been suggested that the duration of widely distributed phasic inhibitory postsynaptic potentials (IPSPs) determines the frequency of the resulting network oscillation. Here, we test this hypothesis in an in vitro model of sharp wave-ripple (SPW-R) complexes, a particularly fast pattern of network oscillations at ∼200 Hz which is involved in memory consolidation. We recorded SPW-R in mouse hippocampal slices in the absence and presence of NCC-711, an inhibitor of GABA uptake. The resulting prolongation of IPSP resulted in reduced occurrence of SPW-R, whereas the superimposed fast oscillations as well as the precision of rhythmic cell synchronization remained stable. Application of Diazepam which is a positive modulator of the GABAA receptor led to consistent results. We conclude that phasic inhibition is a major regulator of network excitability in CA3 (where SPW-Rs are generated), but does not set the frequency of hippocampal ripples.

Reliable optical detection of coherent neuronal activity in fast oscillating networks in vitro.

Cognitive and behavioral functions depend on the activation of stable neuronal assemblies, i.e. distributed groups of co-active neurons within neuronal networks. It is therefore crucial to monitor distributed patterns of activity in real time with single-neuron resolution. Microelectrode recordings allow detection of coincidence between discharges of identified units at high temporal resolution, but are not able to reveal the full spatial pattern of activity in multi-cellular assemblies. Therefore, observation of such distributed sets of neurons is a stronghold of optical techniques, but the required resolution, sensitivity, and speed are still challenging current technology. Here, we report a new approach for monitoring neuronal assemblies, using memory-related network oscillations in rodent hippocampal circuits as a model. The cytosolic calcium-sensitive fluorescent protein GCaMP3.NES was expressed using recombinant adeno-associated viral (rAAV)-mediated gene transfer in CA3 pyramidal neurons of cultured mouse hippocampal slices. After 14-21 days in culture, field potential recordings revealed spontaneous occurrence of sharp wave-ripple network events during which a fraction of local neurons is coherently activated. Using a custom-built epi-fluorescence microscope we could monitor a field of view of 410 µm × 410 µm with single-neuron optical resolution (20× objective, 0.4 NA). We developed a highly sensitive and specific wavelet-based method of cell identification allowing simultaneous observation of more than 150 neurons at frame rates of up to 60 Hz. Our recording configuration and image analysis provide a tool to investigate cognition-related activity patterns in the hippocampus and other circuits.

Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons.

Hippocampal theta (5-10 Hz) and gamma (35-85 Hz) oscillations depend on an inhibitory network of GABAergic interneurons. However, the lack of methods for direct and cell-type-specific interference with inhibition has prevented better insights that help link synaptic and cellular properties with network function. Here, we generated genetically modified mice (PV-Deltagamma(2)) in which synaptic inhibition was ablated in parvalbumin-positive (PV+) interneurons. Hippocampal local field potential and unit recordings in the CA1 area of freely behaving mice revealed that theta rhythm was strongly reduced in these mice. The characteristic coupling of theta and gamma oscillations was strongly altered in PV-Deltagamma(2) mice more than could be accounted for by the reduction in theta rhythm only. Surprisingly, gamma oscillations were not altered. These data indicate that synaptic inhibition onto PV+ interneurons is indispensable for theta- and its coupling to gamma oscillations but not for rhythmic gamma-activity in the hippocampus. Similar alterations in rhythmic activity were obtained in a computational hippocampal network model mimicking the genetic modification, suggesting that intrahippocampal networks might contribute to these effects.

Dendritic axon origin enables information gating by perisomatic inhibition in pyramidal neurons.

Information processing in neuronal networks involves the recruitment of selected neurons into coordinated spatiotemporal activity patterns. This sparse activation results from widespread synaptic inhibition in conjunction with neuron-specific synaptic excitation. We report the selective recruitment of hippocampal pyramidal cells into patterned network activity. During ripple oscillations in awake mice, spiking is much more likely in cells in which the axon originates from a basal dendrite rather than from the soma. High-resolution recordings in vitro and computer modeling indicate that these spikes are elicited by synaptic input to the axon-carrying dendrite and thus escape perisomatic inhibition. Pyramidal cells with somatic axon origin can be activated during ripple oscillations by blocking their somatic inhibition. The recruitment of neurons into active ensembles is thus determined by axonal morphological features.

Field potential signature of distinct multicellular activity patterns in the mouse hippocampus.

Cognitive functions go along with complex patterns of distributed activity in neuronal networks, thereby forming assemblies of selected neurons. To support memory processes, such assemblies have to be stabilized and reactivated in a highly reproducible way. The rodent hippocampus provides a well studied model system for network mechanisms underlying spatial memory formation. Assemblies of place-encoding cells are repeatedly activated during sleep-associated network states called sharp wave-ripple complexes (SPW-Rs). Behavioral studies suggest that at any time the hippocampus harbors a limited number of different assemblies that are transiently stabilized for memory consolidation. We hypothesized that the corresponding field potentials (sharp wave-ripple complexes) contain a specific signature of the underlying neuronal activity patterns. Hence, they should fall into a limited number of different waveforms. Application of unbiased sorting algorithms to sharp wave-ripple complexes in mouse hippocampal slices did indeed reveal the reliable recurrence of defined waveforms that were robust over prolonged recording periods. Single-unit discharges tended to fire selectively with certain SPW-R classes and were coupled above chance level. Thus, field SPW-Rs of different waveforms are directly related to the underlying multicellular activity patterns that recur with high fidelity. This direct relationship between the coordinated activity of distinct groups of neurons and macroscopic electrographic signals may be important for cognition-related physiological studies in humans and behaving animals.

Enriched Environment Modulates Sharp Wave-Ripple (SPW-R) Activity in Hippocampal Slices.

Behavioral flexibility depends on neuronal plasticity which forms and adapts the central nervous system in an experience-dependent manner. Thus, plasticity depends on interactions between the organism and its environment. A key experimental paradigm for studying this concept is the exposure of rodents to an enriched environment (EE), followed by studying differences to control animals kept under standard conditions (SC). While multiple changes induced by EE have been found at the cellular-molecular and cognitive-behavioral levels, little is known about EE-dependent alterations at the intermediate level of network activity. We, therefore, studied spontaneous network activity in hippocampal slices from mice which had previously experienced EE for 10-15 days. Compared to control animals from standard conditions (SC) and mice with enhanced motor activity (MC) we found several differences in sharp wave-ripple complexes (SPW-R), a memory-related activity pattern. Sharp wave amplitude, unit firing during sharp waves, and the number of superimposed ripple cycles were increased in tissue from the EE group. On the other hand, spiking precision with respect to the ripple oscillations was reduced. Recordings from single pyramidal cells revealed a reduction in synaptic inhibition during SPW-R together with a reduced inhibition-excitation ratio. The number of inhibitory neurons, including parvalbumin-positive interneurons, was unchanged. Altered activation or efficacy of synaptic inhibition may thus underlie changes in memory-related network activity patterns which, in turn, may be important for the cognitive-behavioral effects of EE exposure.

Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse Hippocampus In Vitro.

Neurons are highly vulnerable to conditions of hypoxia-ischemia (HI) such as stroke or transient ischemic attacks. Recovery of cognitive and behavioral functions requires re-emergence of coordinated network activity, which, in turn, relies on the well-orchestrated interaction of pyramidal cells (PYRs) and interneurons. We therefore modelled HI in the mouse hippocampus, a particularly vulnerable region showing marked loss of PYR and fast-spiking interneurons (FSIs) after hypoxic-ischemic insults. Transient oxygen-glucose deprivation (OGD) in ex vivo hippocampal slices led to a rapid loss of neuronal activity and spontaneous network oscillations (sharp wave-ripple complexes; SPW-Rs), and to the occurrence of a spreading depolarization. Following reperfusion, both SPW-R and neuronal spiking resumed, but FSI activity remained strongly reduced compared with PYR. Whole-cell recordings in CA1 PYR revealed, however, a similar reduction of both EPSCs and IPSCs, leaving inhibition-excitation (I/E) balance unaltered. At the network level, SPW-R incidence was strongly reduced and the remaining network events showed region-specific changes including reduced ripple energy in CA3 and increased ripple frequency in CA1. Together, our data show that transient hippocampal energy depletion results in severe functional alterations at the cellular and network level. While I/E balance is maintained, synaptic activity, interneuron spiking and coordinated network patterns remain reduced. Such alterations may be network-level correlates of cognitive and functional deficits after cerebral HI.

Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2aN615S), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.

VEGF-D Downregulation in CA1 Pyramidal Neurons Exerts Asymmetric Changes of Dendritic Morphology without Correlated Electrophysiological Alterations.

The morphology of dendritic arbors determines the location, strength and interaction of synaptic inputs. It is therefore important to understand the factors regulating dendritic arborization both during development and in situations of physiological or pathological plasticity. We have recently shown that VEGF-D (Vascular Endothelial Growth Factor D) is required to maintain length and complexity of basal dendrites in mouse hippocampal pyramidal cells. Lack of VEGF-D resulted in long-term memory deficits, suggesting a link between dendritic morphology and cognitive function. Here, we compared the effect of VEGF-D expression on basal versus apical dendrites of CA1 pyramidal cells, as well as its importance for synaptic processing of network oscillations. We report opposing, layer-specific effects of VEGF-D knockdown which resulted in shrinkage of basal and increased complexity of apical dendrites. Synaptic potentials and layer-specific voltage gradients during network oscillations remained, however, unaltered. These findings reveal a high spatial selectivity of VEGF-D effects at the sub-cellular level, and strong homeostatic mechanisms which keep spatially segregated synaptic inputs in a balance.