Biology subjects

Shigemoto, R.

Publications and source records attributed to Shigemoto, R..

18 recordsLinked to original sources

bioRxiv2026

Nanoscale remodeling of synaptic glutamate receptors and calcium channels in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and remains drug-resistant in approximately one-third of patients, for whom surgical resection of the epileptogenic zone is currently the most effective treatment option. One strategy to improve therapeutic outcomes involves identifying the molecular mechanisms and key regulators underlying synaptic function. Although altered glutamatergic neurotransmission is considered a major contributor to epileptic hyperexcitability, the nanoscale organization of key synaptic proteins in the human epileptic cortex is still not well characterized. In particular, it remains unclear whether pre- and postsynaptic proteins undergo synapse-type-specific remodeling in TLE. Here, we used high-resolution freeze-fracture replica immunolabeling to map the nanoscale organization of postsynaptic AMPA receptors (AMPARs) and presynaptic P/Q-type voltage-gated calcium channels (CaV2.1) in glutamatergic synapses of cortical layers II/III of surgically resected human tissue. We examined perilesional, cytologically unremarkable, non-epileptogenic cortical tissue obtained from patients undergoing tumor resection (52-63 years; two female and three male patients) and compared these data with cortical samples from patients with refractory TLE (22-53 years; two female and four male patients). To assess whether pathological remodeling differs across synapse populations, we analyzed both excitatory dendritic spine and shaft synapses. We found a robust, highly consistent increase in AMPAR density at both spine and shaft synapses in TLE patients indicating enhanced postsynaptic excitatory signaling. However, AMPAR spatial reorganization differed between synapse types. Monte Carlo simulations demonstrated that spine synapses largely preserved a random receptor distribution without a significant clustering pattern, whereas shaft synapses exhibited a redistribution from clustering toward random receptor arrangements together with reduced center-preference within the postsynaptic density. In contrast, presynaptic CaV2.1 remodeling was more variable and predominantly associated with excitatory spine synapses. TLE spine synapses exhibited an overall increase in CaV2.1 density together with significantly larger and more numerous CaV2.1 nanoclusters within the active zone. This difference was particularly pronounced in male patients. In comparison, shaft synapses displayed only minor presynaptic alterations. CaV2.1 channels remained highly clustered under both control and epileptic conditions, indicating preservation of core active-zone organizational features despite disease-associated nanoscale remodeling. Together, these findings provide direct ultrastructural support that pathological plasticity in human TLE involves an overall increase in excitatory postsynaptic responsiveness and a target cell-specific increase of excitatory release probability at cortical synapses.

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bioRxiv2026

Physiological learning involves intrasynaptic reorganization of GluA1-containing AMPA receptors

Learning and memory formation depend on persistent modifications of excitatory synaptic transmission in the hippocampus through changes in AMPA receptor (AMPAR) content and properties at potentiated synapses. However, directly demonstrating such changes after physiological, behavior-driven learning in the intact brain has remained technically difficult. Using SDS-digested freeze-fracture replica labeling (SDS-FRL), we examined the density and nanoscale localization of AMPAR subunits GluA1, GluA2, and GluA3 in the mouse hippocampal CA1 pyramidal cells. GluA2 density was higher than GluA1 and GluA3 densities at both synaptic and extrasynaptic sites, consistent with previous studies showing that AMPARs in CA1 pyramidal cells mostly contain GluA2. The extrasynaptic density of GluA3 was substantially lower than those of GluA1 and GluA2, pointing to distinct trafficking mechanisms. GluA1- and GluA2-containing receptors were enriched at synaptic peripheries, whereas GluA3 was more centrally localized and clustered, a subunit-specific intrasynaptic organization consistent with differential roles in plasticity. To investigate learning-induced reorganization, we combined the inhibitory avoidance, hippocampus-dependent contextual learning paradigm with SDS-FRL in the CA1 stratum radiatum. Learning induced a selective increase in synaptic GluA1 density accompanied by a concurrent decrease in GluA2 density, consistent with a compositional shift toward higher-conductance GluA1-containing receptors, specifically in the proximal CA1 area. Strikingly, we found a redistribution of GluA1 from the synaptic periphery toward the center, accompanied by increased clustering. These findings reveal intrasynaptic receptor redistribution alongside subunit composition change, a nanoscale molecular signature at CA3-CA1 synapses, which may constitute a mechanism of hippocampal memory formation in physiological learning.

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bioRxiv2026

Large-scale dimensional behavioral profiling dissociates fear memory from locomotor confounds in mice: The necessity of baseline-normalized metrics

Fear conditioning is widely used to assess associative memory in mice, yet percent freezing conflates memory with baseline locomotor and anxiety-related traits. A systematic survey of recent studies (2020-2025) found that fewer than 1% statistically integrate locomotor activity into freezing analyses. Here, we address this gap using a large-scale dataset of >10,000 mice across >160 comparisons, including genetic mutations, pharmacological interventions and aging, tested in 15 standardized behavioral paradigms. Conventional freezing scores covaried strongly with general locomotor activity, obscuring memory-related phenotypes. Multiple factor analysis identified two principal behavioral dimensions, locomotor activity and learning/memory: conventional freezing aligned with the locomotor dimension, whereas freezing subtraction and the activity suppression ratio mapped onto the memory dimension and improved detection of synaptic plasticity phenotypes. These analyses show that baseline locomotor normalization is essential for interpreting fear conditioning as a memory assay and provide an open framework for selecting and reporting locomotor-normalized metrics.

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bioRxiv2026

Disruption of CaMKII biomolecular condensation induces attention-deficit/hyperactivity disorder-like phenotypes

CaMKII is a multifunctional kinase essential for synaptic plasticity and memory formation. While its canonical role involves enzymatic phosphorylation, recent evidence suggests CaMKII also functions through liquid-liquid phase separation (LLPS) with substrate proteins, including GluN2B-containing NMDA receptors. However, the physiological significance remains unclear. Here, we generated CaMKII subtype knock-in (KI) mice carrying a point mutation (I205K) in the hydrophobic pocket, a key interface required for LLPS. These mice exhibited a complete loss of structural long-term potentiation (sLTP) despite normal spine morphology, marked hyperactivity and profound deficits in aversive memory formation. Atomoxetine, an approved attention-deficit/hyperactivity disorder (ADHD) treatment, ameliorated the hyperactive phenotype. Notably, we identified a patient carrying the I205N variant presenting with ADHD and mild intellectual disability, mirroring the behavioral features observed in I205K KI mice. Additional neurodevelopmental disorder-associated variants within the same hydrophobic pocket similarly disrupted LLPS in vitro. Molecular dynamics simulations revealed these variants destabilize the CaMKII-GluN2B interaction through distinct mechanisms that perturb the dynamic stability of the binding interface. These findings establish CaMKII-mediated phase separation as critical for linking synaptic molecular assembly to cognitive function and provide a unifying molecular basis for synaptic disorganization, hyperactivity, and memory deficits associated with neurodevelopmental disorders. SignificanceCaMKII is essential for synaptic plasticity and memory, yet the contribution of its non-catalytic functions, including liquid-liquid phase separation (LLPS), to brain function remains unclear. Here, we show that disrupting CaMKII LLPS with its synaptic partners impairs synaptic localization, abolishes LTP, and causes profound memory deficits in vivo. A knock-in mouse carrying the I205K mutation showed hyperactivity and impaired learning. This recapitulate the clinical phenotypes of a human patients with the I205N variant, which is associated with ADHD and intellectual disability. Together, these findings establish LLPS as a critical mechanism underlying CaMKII function in the brain and provide a disease-relevant framework for understanding synaptic dysfunction in neurodevelopmental disorders.

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bioRxiv2025

Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula

The medial habenula (MHb) is implicated in regulating emotional responses to aversive events. Studies in zebrafish have identified a remarkable morphological left-right asymmetry in the dorsal habenula (zebrafish equivalent of mammalian MHb)-interpeduncular nucleus (IPN) pathway and its left-sided-specific role in modulating fear responses. However, there is little evidence for structural or functional lateralization in the mammalian MHb-IPN pathway. Here, we investigated the synaptic properties of left- and right-MHb afferents to the IPN and their roles in the expression of conditioned fear in mice. We found that each IPN neuron receives inputs from both left and right MHb, but the left MHb-originating synapses exhibit lower release probability and higher {gamma}-aminobutyric acid type B receptor (GABABR)-mediated potentiation compared to the right MHb-originating synapses. Interestingly, these asymmetrical properties persist in the inversus visceral mutant mice with normal internal organ laterality (situs solitus), but nearly disappear in those with reversed internal organ laterality (situs inversus). Behaviorally, chemogenetic inhibition of cholinergic neurons and conditional deletion of GABABR in the left, but not the right, MHb significantly attenuated cue-dependent fear recall. Our results demonstrate functional asymmetry of the MHb under partial influence of the nodal flow in mice, revealing a predominant role of GABABR-mediated signaling in the left MHb-IPN pathway in modulating fear memories. These findings suggest that lateralized MHb pathways could represent a fundamental principle in the neural regulation of emotion across species, but that they develop differently in zebrafish and mice.

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bioRxiv2023

Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons

It is widely believed that information storage in neuronal circuits involves nanoscopic structural changes at synapses, resulting in the formation of synaptic engrams. However, direct evidence for this hypothesis is lacking. To test this conjecture, we combined chemical potentiation, functional analysis by paired pre-postsynaptic recordings, and structural analysis by electron microscopy (EM) and freeze-fracture replica labeling (FRL) at the hippocampal mossy fiber synapse, a key synapse in the trisynaptic circuit of the hippocampus. Biophysical analysis of synaptic transmission revealed that forskolin-induced chemical potentiation increased the readily releasable vesicle pool size (RRP) and vesicular release probability (Pr) by 146% and 49%, respectively. Structural analysis of mossy fiber synapses by EM and FRL demonstrated an increase in the number of vesicles close to the plasma membrane and the number of clusters of the priming protein Munc13-1, indicating an increase in the number of both docked and primed vesicles. Furthermore, FRL analysis revealed a significant reduction of the nearest neighbor distance (NND) between Munc13-1 and CaV2.1 Ca2+ channels, suggesting reconfiguration of the channel-vesicle coupling nanotopography. Our results indicate that presynaptic plasticity is associated with structural reorganization of active zones (AZs). We propose that changes in potential nanoscopic organization at synaptic vesicle release sites may be correlates of learning and memory at a plastic central synapse.

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bioRxiv2023

LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening

Background and ObjectivesAutoantibodies against the neuronally secreted protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune limbic encephalitis associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening. MethodsWe studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and acute brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies. ResultsLGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels, as presynaptic Cav2.1 channel density, calcium current amplitude, and calcium channel gating were unaffected by LGI1 autoantibodies. In contrast, application of LGI1 autoantibodies homogeneously reduced Kv1.1 and Kv1.2 channel density on the surface of presynaptic boutons. Direct presynaptic patch-clamp recordings revealed that LGI1 autoantibodies cause a pronounced broadening of the presynaptic action potential. Domain-specific effects of LGI1 autoantibodies were analysed at the soma, where polyclonal LGI1 autoantibodies and patient-derived monoclonal autoantibodies targeting the Epitempin-domain but not the Leucin rich repeat-domain induced action potential broadening. DiscussionOur results indicate that LGI1 autoantibodies do not affect calcium channel density or function, but reduce the density of both Kv1.1 and Kv1.2 on presynaptic boutons, thereby broadening the presynaptic action potential and increasing neurotransmitter release. This study provides a molecular explanation for the neuronal hyperactivity induced by LGI1 autoantibodies.

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bioRxiv2023

Multipotent Progenitors Instruct Ontogeny of the Superior Colliculus

The superior colliculus (SC) in the mammalian midbrain is essential for multisensory integration, attention, and complex behavior (Basso and May, 2017; Cang et al., 2018). The mature SC cytoarchitecture is organized into distinct laminae and composed of a rich variety of neuronal and glial cell types (Ayupe et al., 2023; Edwards et al., 1986; May, 2006; Xie et al., 2021; Zeisel et al., 2018). Precise execution of the developmental programs regulating the generation of SC cell-type diversity is essential, because deficits due to genetic mutations have been associated with neurodevelopmental diseases and SC dysfunction (Jure, 2018; McFadyen et al., 2020). However, the fundamentals directing the ontogeny of the SC are not well understood. Here we pursued systematic lineage tracing at the single progenitor cell level in order to decipher the principles instructing the generation of cell-type diversity in the SC. We combined in silico lineage reconstruction with a novel genetic MADM (Mosaic Analysis with Double Markers)-CloneSeq approach. MADM-CloneSeq enables the unequivocal delineation of cell lineages in situ, and cell identity based on global transcriptome, of individual clonally-related cells. Our systematic reconstructions of cell lineages revealed that all neuronal cell types in SC emerge from local progenitors without any extrinsic source. Strikingly, individual SC progenitors are exceptionally multipotent with the capacity to produce all known excitatory and inhibitory neuron types of the prospective mature SC, with individual clonal units showing no pre-defined composition. At the molecular level we identified an essential role for PTEN signaling in establishing appropriate proportions of specific inhibitory and excitatory neuron types. Collectively, our findings demonstrate that individual multipotent progenitors generate the full spectrum of excitatory and inhibitory neuron types in the developing SC, providing a novel framework for the emergence of cell-type diversity and thus the ontogeny of the mammalian SC.

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bioRxiv2022

A two-pool mechanism of vesicle release in medial habenula terminals underlies GABAB receptor-mediated potentiation

GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation induces a transition from tonic to phasic release accompanied by a 4-fold increase in readily releasable pool (RRP) size in MHb terminals, mirrored by a similar increase in the docked vesicle number at the presynaptic active zone (AZ). The tonic and phasic release vesicles have distinct coupling distances. We identified two vesicle-associated molecules, synaptoporin and CAPS2, selectively involved in tonic and phasic release, respectively. Synaptoporin mediates augmentation of tonic release and CAPS2 stabilizes readily releasable vesicles during phasic release. A newly developed "Flash and Freeze-fracture" method revealed selective recruitment of CAPS2 to the AZ during phasic release. Thus, we propose a novel two-pool mechanism underlying the GBR-mediated potentiation of release from MHb terminals.

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bioRxiv2022

Subcortical circuit dysfunctions delay perceptual decision-making in autism models

Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in three independent models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments - a non-perceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1) mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment, and define a non-developmental source of such deficits in ASD.

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bioRxiv2022

Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons

Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an essential role in neuronal activities through interaction with various proteins involved in signaling at membranes. However, the distribution pattern of PI(4,5)P2 and the co-clustering with these proteins on the neuronal cell membranes remain elusive at the electron microscopic level. In this study, we quantitatively investigated the nanoscale distribution of PI(4,5)P2 on the neuronal cell membranes by SDS-digested freeze-fracture replica labeling with cryo-fixed mouse cerebellum. We demonstrate that PI(4,5)P2 makes clusters with a mean size of [~] 1,000 nm2 and these clusters show preferential accumulation in specific membrane compartments depending on cell types. Purkinje cell (PC) spines and granule cell (GC) presynaptic active zones are particularly rich in the PI(4,5)P2 clusters. Furthermore, these clusters are extensively associated with clusters of CaV2.1 and GIRK3 throughout different membrane compartments of PCs, GCs, and molecular layer interneurons. In contrast, these clusters showed compartment-specific association with mGluR1 in PC spines. These results suggest that visualization of the nanoscale PI(4,5)P2 distribution may provide insight into the physiological functions of PI(4,5)P2 in neurons.

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bioRxiv2021

RIM-Binding Protein 2 organizes Ca2+ channel topography and regulates release probability and vesicle replenishment at a fast central synapse

RIM-Binding Protein 2 (RIM-BP2) is a multi-domain protein of the presynaptic active zone (AZ). By binding to Rab-interacting protein (RIM), bassoon and voltage-gated Ca{superscript 2} channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we investigated the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers with bushy cells of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked excitatory postsynaptic currents (EPSCs). Analysis of SV pool dynamics during high frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Ultrastructural analysis by super-resolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in bushy cells of RIM-BP2-deficient mice in vivo. Significance StatementRIM-binding proteins (RIM-BPs) are key organizers of the active zone (AZ). Using a multidisciplinary approach to the calyceal endbulb of Held synapse that transmit auditory information at rates of up to hundreds of Hertz with sub-millisecond precision we demonstrate a requirement for RIM-BP2 for normal auditory signaling. Endbulb synapses lacking RIM-BP2 show a reduced release probability despite normal whole-terminal Ca2+ influx and abundance of the key priming protein Munc13-1, a reduced rate of SV replenishment, as well as an altered topography of CaV2.1 Ca2+ channels, and fewer docked and membrane proximal synaptic vesicles. This hampers transmission of sound onset information likely affecting downstream neural computations such as of sound localization.

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bioRxiv2021

Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons

Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in cerebellar stellate cells (SCs), 3D-reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that, during development, synaptic strength was homogeneously reduced along the somato-dendritic axis, but that dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.

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bioRxiv2020

GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals

The connection from medial habenula (MHb) to interpeduncular nucleus is critical for aversion- and addiction-related behaviors. This pathway is unique in selective expression of R-type voltage-gated Ca2+ channels (Cav2.3) in its terminals, and robust potentiation of release via presynaptic GABAB receptors (GBRs). To understand the mechanism underlying this peculiar GBR effect, we examined the presynaptic localization and function of Cav2.3, GBR, and its auxiliary subunits, K+-channel tetramerization domain-containing (KCTD) proteins. We found selective co-expression of KCTD12b and Cav2.3 at the presynaptic active zone. GBR-mediated potentiation remained intact in KCTD12b KO mice but lasted significantly shorter. This impairment was associated with increased release and an insertion of KCTD8 into the active zone. In heterologous cells, we found direct binding of KCTD8 and KCTD12b to Cav2.3, and potentiation of Cav2.3 currents by KCTD8. The unexpected interaction of Cav2.3 with KCTDs therefore provides a means to scale synaptic strength independent of GBR activation.

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bioRxiv2019

Advantages of acute brain slices prepared at physiological temperature in characterization of synaptic functions

Acute brain slice preparation is a powerful experimental model for investigating the characteristics of synaptic function in the brain. Although brain tissue is usually cut at ice-cold temperature (CT) to facilitate slicing and avoid neuronal damage, exposure to CT causes molecular and architectural changes of synapses. To address these issues, we investigated ultrastructural and electrophysiological features of synapses in mouse acute cerebellar slices prepared at ice-cold and physiological temperature (PT). In the slices prepared at CT, we found significant spine loss and reconstruction, synaptic vesicle rearrangement and decrease in synaptic proteins, all of which were not detected in slices prepared at PT. Consistent with these structural findings, slices prepared at PT showed higher release probability and higher detectability of long-term depression after motor learning compared with slices prepared at CT. These results indicate substantial advantages of the slice preparation at PT for investigating synaptic functions in different physiological conditions.

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bioRxiv2019

Presynaptic α2δ subunits are key organizers of glutamatergic synapses

In nerve cells the genes encoding for 2{delta} subunits of voltage-gated calcium channels (VGCCs) have been linked to synaptic functions and neurological disease. Here we show that 2{delta} subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular 2{delta} subunit triple loss-of-function model, we demonstrate a failure in presynaptic differentiation associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of 2{delta} isoforms as synaptic organizers is highly redundant, as each individual 2{delta} isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Mutating the MIDAS site in 2{delta}-2 dissociates rescuing presynaptic synapsin expression from calcium channel trafficking, suggesting that the regulatory role of 2{delta} subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. Firstly, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Secondly, the dependence of presynaptic differentiation on 2{delta} implicates 2{delta} subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that 2{delta} subunits act as trans-synaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.

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bioRxiv2019

Novelty gates memory formation through ventro-dorsal hippocampal interaction

Novelty facilitates formation of memories. The detection of novelty and storage of contextual memories are both mediated by the hippocampus, yet the mechanisms that link these two functions remain to be defined. Dentate granule cells (GCs) of the dorsal hippocampus fire upon novelty exposure forming engrams of contextual memory. However, their key excitatory inputs from the entorhinal cortex are not responsive to novelty and are insufficient to make dorsal GCs fire reliably. Here we uncover a powerful glutamatergic pathway to dorsal GCs from ventral hippocampal mossy cells (MCs) that relays novelty, and is necessary and sufficient for driving dorsal GCs activation. Furthermore, manipulation of ventral MCs activity bidirectionally regulates novelty-induced contextual memory acquisition. Our results show that ventral MCs activity controls memory formation through an intra-hippocampal interaction mechanism gated by novelty.

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bioRxiv2019

HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can bidirectionally be modulated by HCN channel blockers, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mice cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 {micro}M; estimated endogenous cAMP concentration 13 {micro}M). In accord, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily via altering the resting membrane potential and was associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators an opportunity to finely tune energy consumption and temporal delays across axons in the brain.

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