Biology subjects

Proddutur, A.

Publications and source records attributed to Proddutur, A..

6 recordsLinked to original sources

bioRxiv2026

Primary Cilia Loss in Striatal Neurons Disrupts Synaptic Connectivity and Excitatory Transmission and Drives Metabolomic Remodeling

Disruption of striatal circuits is a central feature of many neurological and psychiatric disorders, yet the mechanisms that maintain afferent connectivity and synaptic function in striatal neurons remain incompletely defined. Primary cilia are signaling organelles present on almost all striatal medium spiny neurons that are enriched in neuromodulatory receptors, suggesting a role in coordinating striatal neuronal communication and biochemical state. Here, we show that conditional ablation of primary cilia from striatal neurons by AAV-Cre-mediated deletion of Ift88 disrupts the afferent connectivity, synaptic function, and chemical signature of the striatum. Monosynaptic rabies tracing revealed an approximately threefold reduction in brain-wide input convergence onto striatal neurons. Whole-cell recordings showed reduced miniature excitatory postsynaptic current amplitude and frequency together with a reduced NMDA:AMPA ratio, consistent with weakened glutamatergic synaptic transmission. Untargeted metabolomics revealed broad remodeling of the striatal chemical profile, predominantly toward decreased measured levels, with lipid-associated pathways most affected alongside reductions in polyamines, glutamate-related metabolites, and neuromodulatory, particularly excitatory, signaling molecules. By contrast, the cortex, which was not targeted by the AAV injection, showed fewer and directionally opposite molecular changes. These findings identify cilia as essential regulators of the structural, synaptic, and molecular integrity required for normal striatal circuit function.

neuroscience↗

bioRxiv2026

Ophthalmate tripeptide is a signaling molecule that regulates striatal neurotransmission

Dopamine has long been regarded as the key neurotransmitter governing motor function through the direct and indirect striatal outflow pathways. However, the tripeptide ophthalmate (ophthalmic acid, OA), a glutathione analog, has recently emerged as another regulator of motor function. While the neural mechanisms by which OA regulates motor function remain unknown, we explored how OA behaves as a striatal neuromodulator. Using radiotracer-based uptake and release assays in mouse striatal tissue, combined with whole-cell electrophysiological recordings, we found that OA is taken up through a saturable, glutathione-competitive transport mechanism and is released in a Ca{superscript 2}-dependent manner upon depolarization, consistent with regulated exocytotic release. OA enhanced depolarization-evoked release of {gamma}-aminobutyric acid (GABA) but not glutamate, indicating selective modulation of distinct neurotransmitter systems. OA and dopamine reciprocally regulated one another: OA enhanced dopamine release, while D2 dopamine receptor activation suppressed OA release. Whole-cell recordings from medium spiny neurons (MSNs) showed that OA increased the amplitude of evoked AMPA receptor-mediated currents and shifted short-term plasticity from facilitation toward depression at excitatory synapses onto direct-pathway MSNs (dMSNs). These findings are consistent with an increase in presynaptic glutamate release probability, while sparing synapses onto indirect-pathway MSNs (iMSNs). Together, these findings establish OA as a striatal neuromodulator that interacts with other neurotransmitter systems and preferentially potentiates direct-pathway transmission. This novel discovery identifies a candidate mechanism within the basal ganglia circuitry that governs motor control, with major relevance to Parkinsons disease and other movement disorders.

neuroscience↗

bioRxiv2025

Multiplexed changes in synaptic transmission underlie stress-induced reduction of persistent firing in the parietal cortex

Repeated exposure to stress disrupts cognitive processes, including attention and working memory. A key mechanism supporting these functions is the ability of neurons to sustain action potential firing, even after a stimulus is no longer present. How stress impacts this persistent neuronal activity is currently unknown. We found that repeated exposure to multiple concurrent stressors during adolescence (aRMS) impedes the ability of layer 5 pyramidal neurons (L5 PNs) in the posterior parietal cortex (PPC) to produce persistent firing. To determine the mechanisms underlying this effect, we complemented computational modelling with whole-cell patch clamp electrophysiology in acute brain slices from male mice. Our model predicted that altered intrinsic excitability, reduced local connectivity, diminished glutamatergic transmission, or enhanced inhibition could explain diminished persistent activity. In ex vivo experiments, we found minimal effect of aRMS on excitability and recurrent connectivity. However, stress exposure altered the properties of excitatory connections between L5 PNs, specifically affecting decay kinetics and short-term synaptic dynamics. In addition, aRMS increased inhibitory tone in the PPC, altering both GABAa and GABAb receptor-mediated responses. Incorporating the observed physiological changes into our network model, we found that no single parameter was sufficient alone to reproduce the stress-induced reduction in persistent firing. Rather, a combination of altered excitatory and inhibitory synaptic transmission was necessary to impact sustained activity. These data suggest that a multitude of converging changes in neural and circuit function underpin the effects of stress on cognitive processes. HighlightsO_LIStress exposure impairs persistent firing in the posterior parietal cortex. C_LIO_LIGABAergic inhibition is enhanced following stress. C_LIO_LIStress alters excitatory transmission between layer 5 pyramidal cells. C_LIO_LICombined changes in inhibition and excitation impact persistent firing. C_LI

neuroscience↗

bioRxiv2023

RECLUSIVE CHANDELIERS: FUNCTIONAL ISOLATION OF DENTATE AXO-AXONIC CELLS AFTER EXPERIMENTAL STATUS EPILEPTICUS

Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.

neuroscience↗

bioRxiv2021

Long-term effects of moderate concussive brain injury during adolescence on synaptic and tonic GABA currents in dentate projection neurons.

Progressive physiological changes in the hippocampal dentate gyrus circuits following traumatic brain injury contribute to temporal evolution of neurological sequelae. Although early posttraumatic changes in dentate synaptic and extrasynaptic GABA currents have been reported, whether they evolve over time and remain distinct between the two projection neuron classes, granule cells and semilunar granule cells, has not been evaluated. We examined changes in tonic GABA currents and spontaneous inhibitory postsynaptic currents (sIPSCs) and in dentate projection neurons one and three month after moderate concussive fluid percussion injury (FPI) in adolescent rats. Granule cell tonic GABA current amplitude remained elevated up to one month after FPI, but decreased to levels comparable to age-matched controls by three months postinjury. Granule cell sIPSC frequency, which we previously reported to be increased one week after FPI, remained higher than in age-matched controls at one month and was significantly reduced three months after FPI. In contrast to the early decrease, tonic GABA current amplitude and sIPSC frequency in semilunar granule cell was not different from controls three months after FPI. The switch in granule cell inhibitory inputs from early increase to subsequent decrease could contribute to the delayed emergence of cognitive deficits and seizure susceptibility after brain injury.

neuroscience↗

bioRxiv2019

Semilunar Granule Cells Maintain Distinct Dendritic Morphology and Inhibition through Postnatal Development and Receive Heightened Inhibition in Adolescence

Semilunar granule cells (SGCs) have been proposed as a morpho-functionally distinct class of hippocampal dentate projection neurons contributing to feedback inhibition and memory processing in juvenile rats. However, the structural and physiological features that can reliably classify granule cells (GCs) from SGCs through postnatal development remain unresolved. Focusing on postnatal days 11-13, 28-42, and >120, corresponding with human infancy, adolescence, and adulthood, we examined the somatodendritic morphology and inhibitory regulation in SGCs and GCs to determine the cell-type specific features. Unsupervised cluster analysis confirmed that morphological features reliably distinguish SGCs from GCs irrespective of animal age. SGCs maintain higher spontaneous inhibitory postsynaptic current (sIPSC) frequency than GCs from infancy through adulthood. Although sIPSC frequency in SGCs was particularly enhanced during adolescence, sIPSC amplitude and cumulative charge transfer declined from infancy to adulthood and were not different between GCs and SGCs. Extrasynaptic GABA current amplitude peaked in adolescence in both cell types and was significantly greater in SGCs than in GCs only during adolescence. Although GC input resistance was higher than in SGCs during infancy and adolescence, input resistance decreased with developmental age in GCs while it progressively increased in SGCs. Consequently, GCs input resistance was significantly lower than SGCs in adults. The data delineate the structural features that can reliably distinguish GCs from SGCs through development. The results reveal developmental differences in passive membrane properties and steady state inhibition between GCs and SGCs which could confound their use in classifying the cell types.

neuroscience↗