Biology subjects

Lieberman, O. J.

Publications and source records attributed to Lieberman, O. J..

4 recordsLinked to original sources

bioRxiv2026

Altered striatal long-term potentiation in the eIF4E- TG ASD mouse model

Autism spectrum disorder (ASD) is associated with deficits in synaptic plasticity across brain regions. While striatal dysfunction is observed in various mouse models of ASD, the effect of ASD-associated genes on striatal plasticity has not been well characterised. We previously showed that overexpression of the SFARI ASD risk gene eIF4E in transgenic (eIF4E-TG) mice produces ASD-like behaviours and impairs dorsal striatal dopamine release. Here, we examined whether eIF4E overexpression alters striatal synaptic transmission and plasticity. Using microscopy, whole-cell electrophysiology, optogenetics and fast-scan cyclic voltammetry, we assessed dendritic morphology and excitatory synaptic properties of spiny projection neurons (SPNs). The eIF4E-TG mice exhibited higher dendritic spine density, elevated AMPA and NMDA receptor-mediated mEPSC frequency, and reduced AMPA mEPSC amplitude. We also observed an increased induction rate and magnitude of long-term potentiation (LTP) in SPNs, which is NMDA receptor-dependent but is not prevented by pharmacological D1 or D2 receptor antagonism under the conditions tested. Finally, we found that somatic and dendritic Ca2+ signals evoked by brief depolarisation are altered in SPNs from eIF4E-TG mice. Together, these findings are consistent with eIF4E overexpression promoting an NMDA receptor-dependent form of striatal LTP that is not prevented by D1/D2 receptor antagonism.

neuroscience↗

bioRxiv2024

5-HT1B receptors mediate dopaminergic inhibition of vesicular fusion and GABA release from striatonigral synapses.

The substantia nigra pars reticulata (SNr), a crucial basal ganglia output nucleus, contains a dense expression of dopamine D1 receptors (D1Rs), along with dendrites belonging to dopaminergic neurons of substantia nigra pars compacta. These D1Rs are primarily located on the terminals of striatonigral medium spiny neurons, suggesting their involvement in the regulation of neurotransmitter release from the direct pathway in response to somatodendritic dopamine release. To explore the hypothesis that D1Rs modulate GABA release from striatonigral synapses, we conducted optical recordings of striatonigral activity and postsynaptic patch-clamp recordings from SNr neurons in the presence of dopamine and D1R agonists. We found that dopamine inhibits optogenetically triggered striatonigral GABA release by modulating vesicle fusion and Ca2+ influx in striatonigral boutons. Notably, the effect of DA was independent of D1R activity but required activation of 5-HT1B receptors. Our results suggest a serotonergic mechanism involved in the therapeutic actions of dopaminergic medications for Parkinsons disease and psychostimulant-related disorders.

neuroscience↗

bioRxiv2024

Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders.

Autism Spectrum Disorders (ASD) consist of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine dopamine neurotransmission in a mouse model of ASD characterized by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal dopamine release. The loss of normal dopamine neurotransmission is due to a defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings reveal an intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility, provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions.

neuroscience↗

bioRxiv2021

Subcellular and regional localization of mRNA translation in midbrain dopamine neurons

Local translation within excitatory and inhibitory neurons is involved in neuronal development and synaptic plasticity. Despite the extensive dendritic and axonal arborizations of central monoaminergic neurons, the subcellular localization of protein synthesis is not well-characterized in these populations. Here, we investigated mRNA localization and translation in midbrain dopaminergic (mDA) neurons, cells with enormous axonal and dendritic projections, both of which exhibit stimulation-evoked dopamine (DA) release. Using highly-sensitive ribosome-bound RNA-sequencing and imaging approaches in mDA axons, we found no evidence for axonal mRNA localization or translation. In contrast, mDA neuronal dendritic projections into the substantia nigra reticulata (SNr) contain ribosomes and mRNAs encoding the major components of DA synthesis, release, and reuptake machinery. Surprisingly, we also observed dendritic localization of mRNAs encoding synaptic vesicle-related proteins, including those involved in vesicular exocytic fusion. Our results are consistent with a role for local translation in the regulation of DA release from dendrites, but not from axons. Our translatome data further defined a molecular signature of the sparse mDA neurons resident in the SNr, including enrichment of Atp2a3/SERCA3, an ER calcium pump previously undescribed in mDA neurons.

neuroscience↗