Biology subjects

Prifti, V.

Publications and source records attributed to Prifti, V..

5 recordsLinked to original sources

bioRxiv2026

Functional ultrasound imaging reveals pathway-specific visual system reorganization in young Cln3-/- mice

CLN3 disease, or juvenile Batten disease, is a neurodegenerative lysosomal storage disorder in which visual impairment is typically the earliest clinical manifestation. Although retinal pathology has been extensively studied, functional alterations within central visual pathways remain poorly understood. Here, we used functional ultrasound (fUS) imaging to characterize visually evoked activity across central visual circuits in young Cln3 knockout (Cln3-/-) mice before the onset of severe retinal degeneration. Visually evoked hemodynamic responses were quantified in regions spanning the geniculostriate and extrageniculate visual pathways, including cortical, thalamic, and midbrain regions. To assess regional pathological burden, accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a pathological marker of CLN3 disease, was examined using immunohistochemistry. We found that Cln3-/- mice exhibited pathway-specific alterations in visually evoked activity. Regions along the extrageniculate pathway, including the midbrain, posterior thalamus, and anterior secondary visual cortex, showed enhanced activation relative to wild-type controls. In contrast, activation within the geniculostriate pathway was reduced in the anterior thalamus and remained unchanged in the primary and posterior secondary visual cortex. SCMAS accumulation was elevated across all examined visual regions in Cln3-/- mice relative to wild-type controls, with greater accumulation observed in geniculostriate regions than in extrageniculate regions. These findings demonstrate early pathway-specific functional and pathological alterations in the visual system of Cln3-/- mice, suggesting pathway-level reorganization of central visual processing. This study advances understanding of central visual dysfunction in CLN3 disease and highlights fUS imaging as a sensitive approach for detecting early functional abnormalities in neurodegenerative disorders.

neuroscience↗

bioRxiv2026

Distinct Auditory Thalamocortical Pathologies Underlie Emerging Neurophysiological Dysfunction in a Cln3 Mouse Model of Batten Disease

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3-/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3-/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3-/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3-/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/729359v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8dc148org.highwire.dtl.DTLVardef@8c918borg.highwire.dtl.DTLVardef@a7483dorg.highwire.dtl.DTLVardef@77d171_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISCMAS accumulates across the auditory thalamocortical circuit in Cln3-/- mice C_LIO_LIAccumulation shows distinct age- and sex-dependent regional trajectories C_LIO_LICln3-/- mice exhibit progressive alterations in auditory evoked potentials C_LIO_LIThalamic pathology is strongly associated with the early auditory N1 response C_LIO_LIHistology-EEG integration links circuit pathology to auditory dysfunction C_LI

neuroscience↗

bioRxiv2025

Response dynamics of discrete subiculum->retrosplenial cortex projections underlying trace fear conditioning

Associating events separated in time depends on the CA1, subiculum (SUB), and retrosplenial cortex (RSP). The degree to which their connectivity and underlying circuit mechanisms contribute to the association of such temporally discontiguous events is not known. Here we showed, using trace fear conditioning (TFC), wherein mice learn to associate tone and shock separated by a temporal trace, that molecularly distinct excitatory VGluT1+ and VGluT2+ SUB[->]RSP projections subserve the associative and temporal components of TFC. During trace memory formation, VGluT2+ SUB[->]RSP projections showed increased and decreased bulk calcium activity at tone and trace onset, respectively, an activity pattern that was reestablished during memory recall. Such pattern was not observed in CA subfields, suggesting that associative and temporal components of TFC are integrated at the SUB or SUB[->]RSP synapses before being presented to the RSP. Our findings establish a circuit mechanism for representing complex temporal information in episodic memory.

neuroscience↗

bioRxiv2025

Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease

CLN3 disease is a prevalent form of Neuronal Ceroid Lipofuscinosis (NCL) caused by inherited mutations in the CLN3 gene, with symptoms such as vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates neurological assessment of brain pathophysiology underlying cognitive decline, while the small number of CLN3 mutation cases in humans hinders the study of sex differences. Building on our recent progress in assessing auditory neurophysiological changes in CLN3 patients, we developed a parallel approach using electroencephalography arrays in Cln3 knockout (Cln3-/-) mice to investigate the longitudinal progression of auditory processing deficits in both sexes. We employed a duration mismatch negativity (MMN) paradigm, similar to that used in our CLN3 patient studies, to assess the automatic detection of pattern changes in a sequence of stimuli. Wild-type mice of both sexes showed robust duration MMN responses when assessed longitudinally in the same subjects from 3 to 9 months of age. In contrast, female Cln3-/- mice developed consistent MMN deficits throughout this age range, while male Cln3-/- mice exhibited MMN deficits at younger ages that were mitigated at older ages. Analyses of auditory brainstem responses indicate that MMN abnormalities in Cln3-/- mice are not due to peripheral hearing loss. Instead, these deficits originate centrally from sex-specific and age-related changes in auditory evoked potentials elicited by standard and deviant stimuli. Our findings reveal a sex-specific progression of central auditory processing deficits in Cln3-/- mice, supporting auditory duration MMN as a translational neurophysiological biomarker for mechanistic studies and therapeutic development. Significance StatementCLN3 disease is an inherited neurodegenerative disorder with progressive decline in cognitive functioning and verbal abilities. The neuropathophysiological mechanisms underlying this decline remain poorly understood, highlighting the urgent need for objective neurological biomarkers to advance mechanistic insights and therapeutic development. Our identification of central auditory processing and change detection deficits in Cln3-/- mice, mirroring findings from our recent studies in CLN3 patients, validates auditory MMN as a translational neurophysiological biomarker bridging pre-clinical and clinical research. Moreover, our discovery of sex-specific, non-linear progression of MMN deficits emphasizes the necessity of developing disease management strategies tailored to each sex. This finding also provides a foundation for investigating both pathogenic and compensatory neural mechanisms to inform the development of individualized treatments.

neuroscience↗

bioRxiv2024

Structural analyses of apolipoprotein A-IV polymorphisms Q360H and T347S elucidate the inhibitory effect against thrombosis

Apolipoprotein A-IV (apoA-IV) is an abundant lipid-binding protein in blood plasma. We previously reported that apoA-IV, as an endogenous inhibitor, competitively binds platelet IIb{beta}3 integrin from its N-terminal residues, reducing the potential risk of thrombosis. This study aims to investigate how the apoA-IVQ360H and apoA-IVT347S mutations affect the structure and function of apoA-IV. These mutations are linked to increased risk of cardiovascular diseases due to multiple single-nucleotide polymorphisms in the C-terminal region of apoA-IV. We postulate the structural hindrance caused by the C-terminal motifs may impede the binding of apoA-IV to platelets at its N-terminal binding site. However, the mechanistic impact of Q360H and T347S polymorphisms on this intermolecular interaction and their potential contribution to the development of cardiovascular disease have not been adequately investigated. To address this, recombinant forms of human apoA-IVWT, apoA-IVQ360H, apoA-IVT347S variants were produced, and the structural stability, dimerization, and molecular dynamics of the C-terminus were examined utilizing biophysical techniques including fluorescence anisotropy, fluorescence spectrophotometry, circular dichroism, and biolayer interferometry methods. Our results showed a deceased fraction of -helix structure in apoA-IVQ360H and apoA-IVT347S compared to the wildtype, and the inhibitory effect of dimerized apoA-IV on platelet aggregation was reduced in apoA- IVQ360H and apoA-IVT347S variants. Binding kinetics of examined apoA-IV polymorphisms to platelet IIb{beta}3 suggest a potential mechanism for increased risk of cardiovascular diseases in individuals with apoA-IVQ360H and apoA-IVT347S polymorphisms.

biochemistry↗