Biology subjects

Lur, G.

Publications and source records attributed to Lur, G..

5 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↗

bioRxiv2018

Simultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits

Spontaneous and sensory-evoked activity propagates across spatial scales in the mammalian cortex but technical challenges have generally precluded establishing conceptual links between the function of local circuits of neurons and brain-wide network dynamics. To solve this problem, we developed a method for simultaneous cellular-resolution two-photon calcium imaging of a local microcircuit and mesoscopic widefield calcium imaging of the entire cortical mantle in awake, behaving mice. Our method employs an orthogonal axis design whereby the mesoscopic objective is oriented downward directly above the brain and the two-photon objective is oriented horizontally, with imaging performed through a glass right angle microprism implanted in the skull. In support of this method, we introduce a suite of analysis tools for relating the activity of individual cells to distal cortical areas, as well as a viral method for robust and widespread gene delivery in the juvenile mouse brain. We use these methods to characterize the diversity of associations of individual, genetically-defined neurons with cortex-wide network motifs.

neuroscience↗

bioRxiv2018

Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission.

A growing body of literature has demonstrated the potential for ketamine in the treatment of major depression. Sub-anesthetic doses produce rapid and sustained changes in depressive behavior, both in patients and rodent models, associated with reorganization of glutamatergic synapses in the prefrontal cortex (PFC). While ketamine is known to regulate NMDA-type glutamate receptors (NMDARs), the full complement of downstream cellular consequences for ketamine administration are not well understood. Here, we combine electrophysiology with 2-photon imaging and glutamate uncaging in acute slices of mouse PFC to further examine how ketamine alters glutamatergic synaptic transmission. We find that four hours after ketamine treatment, glutamatergic synapses themselves are not significantly affected. However, expression levels of the neuromodulatory Regulator of G-protein Signaling (RGS4) are dramatically reduced. This loss of RGS4 activity disrupts the normal compartmentalization of synaptic neuromodulation. Thus, under control conditions, 2 adrenergic receptors and GABAB receptors selectively inhibit AMPA-type glutamate receptors (AMPARs) and NMDARs, respectively. After ketamine-induced loss of RGS4 activity, this selectivity is lost, with both modulatory systems broadly inhibiting glutamatergic transmission. These results demonstrate a novel mechanism by which ketamine can influence synaptic signaling and provide new avenues for the exploration of therapeutics directed at treating neuropsychiatric disorders, such as depression.

neuroscience↗