Biology subjects

Lopez-Begines, S.

Publications and source records attributed to Lopez-Begines, S..

2 recordsLinked to original sources

bioRxiv2025

Cholinergic Modulation of Chandelier Cells via Heteromeric Nicotinic Receptors in Prefrontal Cortex

Chandelier cells (ChCs) are a highly specialized subtype of GABAergic interneurons and one of the most distinctive elements of cortical circuitry, exerting powerful and strategic control over pyramidal neuron output by selectively innervating their axon initial segment. They are particularly abundant in the prefrontal cortex, where cholinergic inputs modulate cognitive functions and shape ChC axonal development, but the way in which the cholinergic system--a master modulator of attention and arousal--regulates these cells in the adult brain has long remained unexplored. In this study, by employing an intersectional genetic strategy in adult mice, we reveal that ChCs in the secondary motor cortex are direct targets of cholinergic modulation. Through patch-clamp recordings and functional imaging, we demonstrate that acetylcholine persistently activates ChCs via heteromeric nicotinic receptors containing the {beta}2 subunit, triggering robust depolarization and a significant increase in intrinsic excitability. This regulation does not rely on fast synaptic transmission; instead, it arises from a diffuse and sustained cholinergic signaling mode, orchestrated from the basal forebrain. Intriguingly, our in vivo observations show that ChC activity is positively correlated with behavioral markers of high arousal, such as locomotion and pupil dilation--a signature of activity that diminished upon the blockade of nicotinic receptors. Our findings strongly suggest that ChCs serve as a link between global arousal and local cortical control, thereby offering deeper insights into the mechanisms of state-dependent information processing.

neuroscience↗

bioRxiv2023

Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency

Kufs disease/CLN4 is an autosomal dominant neurodegenerative disorder that affects young adults, caused by mutations in the DNAJC5 gene that encodes the synaptic vesicle co-chaperone Cysteine String Protein (CSP/DNAJC5). The Leu115Arg and Leu116{Delta} mutations in humans are known to independently cause the disease, although the underlying mechanisms are unknown. To investigate the disease mechanisms in vivo, we generated three independent mouse lines overexpressing different versions of CSP/DNAJC5 under the neuron-specific Thy1 promoter: wild-type (WT), Leu115Arg, and Leu116{Delta}. Mice expressing mutant CSP/DNAJC5 are viable and do not show any significant increase in morbidity or mortality. However, we observed the presence of pathological lipofuscinosis in the mutants, indicated by autofluorescent punctate structures labeled with antibodies against ATP synthase subunit C, which were absent in the WT transgenic line. Additionally, transmission electron microscopy revealed intracellular structures resembling granular osmiophilic deposits (GRODs), observed in Kufs disease patients, in the mutants but not in non-transgenic controls or the WT transgenic mice. Notably, conventional, or conditional knockout mice lacking CSP/DNAJC5 did not exhibit any signs of increased lipofuscinosis or GRODs. Our novel mouse models thus provide a valuable tool to investigate the molecular mechanisms underlying Kufs disease/CLN4. We conclude that DNAJC5 mutations cause neuronal lipofuscinosis through a cell-autonomous gain of a novel but pathological function of CSP/DNAJC5.

neuroscience↗