Biology subjects

Nadkarni, S.

Publications and source records attributed to Nadkarni, S..

11 recordsLinked to original sources

bioRxiv2025

Structural specialization of mossy fiber boutons is necessary for their unique computational functions

Sparsely active granule cells in the dentate gyrus (DG) project onto CA3 pyramidal neurons through mossy fibers (MF), forming a feedforward network that ensures even similar inputs activate distinct and minimally overlapping populations of CA3 neurons. This process, known as pattern separation, is a key computational feature at this synapse. However, such sparse activity and connectivity increase the risk of information loss, as multiple presynaptic inputs are typically required to elicit a postsynaptic action potential. Interestingly, MF synapses exhibit robust short-term plasticity (STP), enabling a dynamic increase in release probability during brief bursts of presynaptic activity. This mechanism ensures that a short, high-frequency burst from a single granule cell can reliably generate a spike in its postsynaptic CA3 target. Unlike other hippocampal synapses, MF boutons are large, with multiple active zones, each coupled to a cluster of voltage-dependent calcium channels (VDCCs). MF boutons also possess a large readily releasable pool of vesicles. The functional consequences of this unusual synaptic design remain largely unexplored. In fact, the MF synapse is often depicted as a synapse with multiple sites, each behaving as an independent transmission line, analogous to several CA3 boutons contacting a single CA1 dendrite. We developed a physiologically realistic spatial model of the MF bouton to investigate how its peculiar structural and functional properties affect synaptic signaling and plasticity. Contrary to earlier assumptions, our computational model revealed, release sites are not independent transmission units. Crosstalk between calcium domains is necessary for the observed strong STP and for the timely activation of CA3 neurons. VDCCs in the MF bouton are only loosely coupled to active zones, and the distance between active zones is relatively large. In addition to the synaptic design and the known role of calbindin-D28k and synaptotagmin-7 in STP, we find that loose coupling of VDCCs to active zones and large inter-AZ distances are crucial. These features keep the basal release probability low, and their combined action is required to generate the facilitation that triggers postsynaptic action potentials in response to bursts filtering out non-informative dentate activity, and provides a strong rationale for the mossy fibers synaptic architecture.

neuroscience↗

bioRxiv2025

Isolation of Secretory Immunoglobulin A (sIgA) from nasal secretions collected in saline and Viral Transport Medium.

Secretory immunoglobulin A (sIgA) is the major immunoglobulin found on all mucosal surfaces, including the nasal cavity and the lining of the gut. It is the first line of defence against pathogens which enter through the nasal cavity or mouth. sIgA1 binds to a lectin isolated from the tropical jackfruit, known as jacalin. Jacalin binds specifically to the D-galactose moiety of sIgA1 and not to sIgA2 which has different sugars. Here we describe a simple and inexpensive method to isolate jacalin from jackfruit seeds, prepare jacalin-Sepharose conjugated beads and isolate sIgA1 from nasal secretion collected in saline as well as in Viral Transport Medium (VTM). The sIgA identity was confirmed by Western blotting using specific antibodies against sIgA heavy chain. Our approach has potential implications as studying sIgA in nasal secretions provides a direct measure of the effectiveness of nasal vaccines at the site of pathogen entry, making it a critical biomarker for both vaccine development and evaluation. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

immunology↗

bioRxiv2025

Nanoscale Lattice Organization of Molecular Condensates Drives Compositional Degeneracy in Synaptic Plasticity

Synaptic plasticity is essential for neuronal communication, involving coordinated structural, molecular and functional changes that are shaped by the nanoscale alterations of the active zone and postsynaptic density. Emerging evidence suggests that synapses function as complex information processing machines, where unique molecular assemblies shape transmission properties. Central to this is the organization of voltage-gated calcium channels (VGCCs) and Bassoon within active zones. Utilizing advanced techniques like liquid-liquid phase separation, super-resolution microscopy, and data-driven models of synaptic transmission, we reveal how nanoscale "compositional degeneracy" in Bassoon and VGCCs enables synapses to achieve functional adaptability through multiple molecular configurations. By modulation of local uncertainty and implementing probabilistic inference, synapses fine-tune transmission efficiency by regulating dynamic entropy and free energy. These principles are especially evident during homeostatic scaling, where synaptic scaling mechanisms differ with neuronal maturity. This study highlights how distinct thermodynamic states in VGCC and Bassoon organization optimize information transfer at different plasticity stages. Our findings propose a refined framework for understanding synaptic transmission as an adaptable, entropy-modulated process, balancing resilience and efficiency.

neuroscience↗

bioRxiv2024

Laser Speckle Particle Sizer (SPARSE) Informs the Size Distribution of Tissue Granularities

Particle sizing of biomaterials and tissues holds profound implications across diverse industrial and clinical disciplines. Conventional approaches such as dynamic light scattering (DLS) are restricted to dilute liquids, and unable to assess particle size distribution in intact, untampered biomaterials and tissues in their native state. Here, we introduce the laser Speckle PARticle SizEr (SPARSE), which leverages the size-dependent attributes of polarized back-scattered laser speckle to characterize the average radius of a continuum of endogenous scattering particles, in the 10nm-10m range, in biological fluids and soft tissues in their native state. The SPARSE approach exploits cross- and co-polarized attributes of spatial and temporal laser speckle intensity fluctuations to quantify the average particle size in various specimens, including polystyrene microspheres, milk, whole blood specimens, and intact soft tissues, without prior knowledge or explicit account of refractive index and scattering concentrations. Through scanning the laser beam across the tissue surface, we establish the capability of SPARSE to evaluate a spatial map of heterogenous scattering particle sizes with a resolution of a few 10s of m that closely mirrors histopathological microstructures in benign and carcinoma breast tissue specimens. By enabling the size characterization of intact tissues and biomaterials across a continuum of granularities, non-destructively in native specimens, SPARSE opens substantial opportunities for quality control in industrial applications, drug development, and advanced clinical diagnostics.

biophysics↗

bioRxiv2022

Placental inflammation leads to abnormal embryonic heart development

Placental and embryonic heart development occurs in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease (CHD), an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to CHD remain unresolved. In the current study we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable to migrate to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Finally, we demonstrate that tempering placental inflammation can rescue this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. Taken together, our observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development.

immunology↗

bioRxiv2020

Role of slow temporal dynamics in reliableactivity of stochastically driven neurons

Neuronal networks maintain robust patterns of activity despite a backdrop of noise from various sources. Mutually inhibiting neurons is a standard network motif implicated in rhythm generation. In an elementary network motif of two neurons capable of swapping from an active state to a quiescent state, we ask how different sources of stochasticity alter firing patterns. In this system, the alternating activity occurs via combined action of a calcium-dependent potassium current, sAHP (slow afterhyperpolarization), and a fast GABAergic synapse. We show that simulating extrinsic noise arising from background activity extends the dynamical range of neuronal firing. Extrinsic noise also has the effect of increasing the switching frequency via a faster build-up of sAHP current. We show that switching frequency as a function of input current has a non-monotonic behavior. Interestingly the noise tolerance of this system varies with the input current. It shows maximum robustness to noise at an input current that corresponds to the minimum switching frequency between the neurons. The slow decay time scale of sAHP conductance allows neurons to act as a low-pass filter, attenuate noise, and integrate over ion channel fluctuations. Additionally, we show that the slow inactivation time of the sAHP channel allows the neuron to act as an action potential counter. We propose that this intrinsic property of the current allows the network to maintain rhythmic activity critical for various functions, despite the noise, and operate as a temporal integrator.

neuroscience↗

bioRxiv2019

Local design principles at hippocampal synapsesrevealed by an energy-information trade-off

Synapses across different brain regions display distinct structure-function relationships. We investigate the interplay of fundamental design principles that shape the transmission properties of the excitatory CA3-CA1 pyramidal cell connection, a prototypic synapse for studying the mechanisms of learning in the hippocampus. This small synapse is characterized by probabilistic release of transmitter, which is markedly facilitated in response to naturally occurring trains of action potentials. Based on a physiologically realistic computational model of the CA3 presynaptic terminal, we show how unreliability and short-term dynamics of vesicle release work together to regulate the trade-off of information transfer versus energy use. We propose that individual CA3-CA1 synapses are designed to operate at close to maximum possible capacity of information transfer in an efficient manner. Experimental measurements reveal a wide range of vesicle release probabilities at hippocampal synapses, which may be a necessary consequence of long-term plasticity and homeostatic mechanisms that manifest as presynaptic modifications of release probability. We show that the timescales and magnitude of short-term plasticity render synaptic information transfer nearly independent of differences in release probability. Thus, individual synapses transmit optimally while maintaining a heterogeneous distribution of presynaptic strengths indicative of synaptically-encoded memory representations. Our results support the view that organizing principles that are evident on higher scales of neural organization percolate down to the design of an individual synapse.

neuroscience↗

bioRxiv2019

Amyloid pathology disrupts gliotransmitter release in astrocytes

Accumulation of amyloid-{beta} peptide (A{beta}), a hallmark of Alzheimers disease (AD), is associated with synchronous hyperactivity and dysregulated Ca2+ signaling in hippocampal astrocytes. However, the consequences of altered Ca2+ signaling on the temporal dynamics of Ca2+ and gliotransmitter release events at astrocytic microdomains are not known. We have developed a detailed biophysical model of microdomain signaling at a single astrocytic process that accurately describes key temporal features of Ca2+ events and Ca2+-mediated kiss-and-run and full fusion exocytosis. Using this model, we ask how aberrant plasma-membrane Ca2+ pumps and mGluR activity, molecular hallmarks of A{beta} toxicity that are also critically involved in Ca2+ signaling, modify astrocytic feedback at a tripartite synapse. We show that AD related molecular pathologies increase the rate and synchrony of Ca2+ and exocytotic events triggered by neuronal activity. Moreover, temporal precision between Ca2+ and release events, a mechanism indispensable for rapid modulation of synaptic transmission by astrocytes, is lost in AD astrocytic processes. Our results provide important evidence on the link between AD-related molecular pathology, dysregulated calcium signaling and gliotransmitter release at an astrocytic process.

neuroscience↗

bioRxiv2018

Intracellular calcium stores mediate a synapse-specific form of metaplasticity at hippocampal dendritic spines

Long-term plasticity mediated by NMDA receptors supports input-specific, Hebbian forms of learning at excitatory CA3-CA1 connections in the hippocampus. An additional layer of stabilizing mechanisms that act globally as well as locally over multiple time scales may be in place to ensure that plasticity occurs in a constrained manner. Here, we investigate the potential role of calcium (Ca2+) stores associated with the endoplasmic reticulum (ER) in the local regulation of plasticity dynamics at individual CA1 synapses. Our study is spurred by (1) the curious observation that ER is sparsely distributed in dendritic spines, but over-represented in large spines that are likely to have undergone activity-dependent strengthening, and (2) evidence suggesting that ER motility within synapses can be rapid, and accompany activity-regulated spine remodeling. Based on a physiologically realistic computational model for ER-bearing CA1 spines, we characterize the contribution of IP3-sensitive Ca2+ stores to spine Ca2+ dynamics during activity patterns mimicking the induction of long-term potentiation (LTP) and depression (LTD). Our results suggest graded modulation of the NMDA receptor-dependent plasticity profile by ER, which selectively enhances LTD induction. We propose that spine ER can locally tune Ca2+-based plasticity on an as-needed basis, providing a braking mechanism to mitigate runaway strengthening at potentiated synapses. Our model suggests that the presence of ER in the CA1 spine may promote re-use of synapses with saturated strengths.

neuroscience↗

bioRxiv2018

Presynaptic Endoplasmic Reticulum Contributes Crucially to Short-term Plasticity in Small Hippocampal Synapses

Short-term plasticity (STP) of the presynaptic terminal maintains a brief history of activity experienced by the synapse that may otherwise remain unseen by the postsynaptic neuron. These synaptic changes are primarily regulated by calcium dynamics in the presynaptic terminal. A rapid increase in intracellular calcium is initiated by the opening of voltage-dependent calcium channels in response to depolarization, the main source of calcium required for vesicle fusion. Separately, electron-microscopic studies of hippocampal CA3-CA1 synapses reveal the strong presence of endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP at the presynaptic terminal remains unexplored. To investigate the contribution of ER in modulating calcium dynamics in small hippocampal boutons, we performed in silico experiments in a physiologically-realistic canonical synaptic geometry based on reconstructions of CA3-CA1 Schaffer collaterals in the rat hippocampus. The model predicts that presynaptic calcium stores are critical in generating the observed paired-pulse ratio (PPR) of normal CA3-CA1 synapses. In control synapses with intact ER, SERCA pumps act as additional calcium buffers, lowering the intrinsic release probability of vesicle release and increasing PPR. In addition, the presence of ER allows ongoing activity to trigger calcium influx from the presynaptic ER via ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs). Intracellular stores and their associated machinery also allows a synapse with a low release probability to operate more reliably due to attenuation of calcium fluctuations. Finally, blocking ER activity in the presynaptic terminal mimics the pathological state of a low facilitating synapse characterized in animal models of Alzheimers disease, and underscores the critical role played by presynaptic stores in normal function.

neuroscience↗

bioRxiv2018

Biophysical basis of disruption in alpha rhythm in Alzheimer’s disease

Alpha is one of the most prominent rhythms (7.5-12.5 Hz) detected in electroencephalography (EEG) during wakeful relaxation with closed eyes. In response to elevated ambient acetylcholine levels, a subclass of thalamic pacemaker cells generate alpha. This rhythm is intrinsic to the cell and is robustly orchestrated by an interplay of hyperpolarization activated cyclic nucleotide gated channels(HCN) and calcium-ion channels. It has been shown that decreased expression of HCN channels is correlated to Alzheimer's Diseased (AD). In early stages of AD, alpha is known to be down-regulated and lowered in coherence. We use this well characterized and quantified rhythm to understand the changes in ion channel properties that lead to disruption of alpha as seen in AD in a biophysically detailed network model of the thalamo-cortical circuit that generates the alpha-rhythm. Our computational model allows us to explore the causal links between alpha rhythms, HCN channels and amyloid-beta aggregation. The most commonly used drugs(acetylcholinesterase inhibitors) in AD increase the duration and level of acetylcholine and provide temporary symptomatic relief in some cases. Our simulations show how increasing acetylcholine can provide rescue for a small range of aberrant HCN expression. We hypothesize that reduced alpha rhythm frequency and coherence is a result of down-regulated HCN expression, rather then compromised cholinergic modulation(as is currently thought). The model predicts that lowering of the alpha-rhythm can modify the network activity in the thalamo-cortical circuit and lead to an increase in the inhibitory drive to the thalamus.

neuroscience↗