Biology subjects

Kamesh, A.

Publications and source records attributed to Kamesh, A..

6 recordsLinked to original sources

bioRxiv2026

Sex- and age-dependent control of dopamine function by LRRK2, and rapid reversal of dopamine release deficits in the LRRK2-G2019S knock-in mouse model of Parkinson's Disease.

No disease-modifying therapy exists for Parkinson's disease (PD). At diagnosis (~65y), ~70% of nigrostriatal dopamine (DA) axons may have degenerated, so identifying when and how striatal axon function declines is critical. LRRK2 hyperactivity is observed in LRRK2 and VPS35 familial cases, and also idiopathic PD. Thus suggests LRRK2 hyperfunction is a common pathophysiological feature of PD. LRRK2 inhibitors are currently in human trials, yet their effects on brain circuit function are poorly characterized. By optical imaging of iGluSnFR and dLight we measured striatal glutamate and DA release in WT, LRRK2 G2019S (LKI) and VPS35 D620N (VKI) knock-in mice, across adult ages and sexes, with and without LRRK2 inhibition. In WT mice, ongoing LRRK2 activity regulated DA release in an age- and sex-dependent manner. Acute inhibition reversed basal sex differences in striatal glutamate and DA release in aged mice, and potentiated DA release more in middle-aged females than males. In LKI mice, DA release declined progressively, first in males, then females, after maturation to full adulthood, and remained impaired in very old LKI and VKI mice. Release deficits in aged LKI and VKI mice were resistant to acute LRRK2 inhibition, but 2h inhibition rapidly reversed deficits in middle-aged LKI males and females. We conclude that LRRK2 activity, and inhibition effects, depend on age, sex, and genotype, with direct implications for the design and timing of current LRRK2 inhibitor clinical trials for PD.

neuroscience↗

bioRxiv2026

Behavioural hyperactivity and risk-taking in young-adult male mice correlate with increased dopamine release in dorsal, but not ventral, striatum

Adolescence is characterized by increased novelty seeking, impulsivity, locomotion and risk-taking, behaviours that facilitate the transition to adulthood but may also increase vulnerability to psychiatric illness. Maturation of dopamine (DA) transmission within the striatum is thought to contribute to these behavioural changes. However, the developmental trajectory of striatal DA release remains unclear, with conflicting evidence regarding age- and sex-dependent changes, particularly across dorsal and ventral striatal regions. Complicating interpretation, many studies classify mice younger than 2 months as 'adults,' potentially obscuring important developmental differences. Here, we examined how age, sex and striatal subregion influence DA release during adolescence and early adulthood. DA release was measured in dorsal and ventral striatal brain slices from male and female C57BL/6J mice at 2 and 4 months of age, corresponding to adolescence and young adulthood. Ultrafast imaging of the genetically encoded DA sensor, dLight, was used to quantify extracellular DA transients evoked by low- and high-frequency electrical stimulation. Glutamatergic and cholinergic transmission was pharmacologically blocked to isolate DA release intrinsic to dopaminergic axons. DA release measures were related to exploratory and locomotor behaviour. We identified a male-specific increase in dorsal striatal DA release between 2 and 4 months of age that coincided with increased locomotion and risk-taking. In contrast, DA release in the ventral striatum did not show comparable age- or sex-dependent changes. These differences were not attributable to altered glutamatergic or cholinergic contributions to DA release. Together, these findings demonstrate that maturation of striatal DA transmission is region- and sex-dependent, with prominent developmental changes occurring in the dorsal striatum during the transition from adolescence to adulthood. These findings help reconcile conflicting reports of developmental DA release and emphasize the importance of considering age, sex and striatal subregion when defining mature dopaminergic function in rodents.

neuroscience↗

bioRxiv2024

Emergent glutamate & dopamine dysfunction in VPS35(D620N) knock-in mice and rapid reversal by LRRK2 inhibition

The D620N variant in Vacuolar Protein Sorting 35 (VPS35) causes autosomal-dominant, late- onset Parkinsons disease. VPS35 is a core subunit of the retromer complex that canonically recycles transmembrane cargo from sorting endosomes. Although retromer cargoes include many synaptic proteins, VPS35s neuronal functions are poorly understood. To investigate the consequences of the Parkinsons mutation, striatal neurotransmission was assessed in 1-, 3- & 6-month-old VPS35 D620N knock-in (VKI) mice. Spontaneous and optogenetically- evoked corticostriatal glutamate transmission was increased in VKI striatal spiny projection neurons by 6 months, when total striatal glutamate release, quantified by iGluSnFR imaging, showed similarities to wild-type. dLight imaging revealed robust increases in VKI striatal dopamine release by 6 months, which were reversed with acute ex vivo leucine-rich repeat kinase 2 (LRRK2) inhibition. We conclude that increased glutamate and dopamine transmission in VKI mice progressively emerges in young-adulthood, and that dopamine dysfunction is likely the result of sustained, rapidly-reversible, LRRK2 hyperactivity.

neuroscience↗

bioRxiv2023

Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provide alternative therapeutic strategies.

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting about 1% of the world population. The first line treatment, lithium (Li), is effective in only a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from BD patients responsive (LR) or not (LNR) to lithium and combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics to report mechanistic insights into neuronal hyperactivity in BD, and Lis mode of action. We show a selective rescue of neuronal hyperactivity by Li in BD LR neurons through changes in Na+ currents. The whole transcriptome sequencing revealed altered gene expression in BD neurons in pathways related to glutamatergic transmission, and Li selectively altered those involved in cell signaling and ion transport/channel activity. We found the therapeutic effect of Li in BD LR patients was associated with Akt signaling and confirmed that an Akt activator mimics Li effect in BD LR neurons. Further, we showed that AMP-activated protein kinase (AMPK) reduces neural network activity and sodium currents in BD LNR patients. These findings suggest the potential for novel treatment strategies in BD, such as Akt activators in BD LR cases, and the use of AMPK activators for BD LNR patients.

neuroscience↗

bioRxiv2021

Surface GluA1 and glutamate transmission are increased in VPS35 D620N neurons and altered by LRRK2 kinase inhibition

Vacuolar protein sorting 35 (VPS35) regulates receptor recycling from endosomes. A missense mutation in VPS35 (D620N) leads to autosomal-dominant, late-onset Parkinsons disease. Here, we use a VPS35 D620N knock-in mouse to study the neurobiology of this mutation. In brain tissue, we confirm previous findings that the mutation results in reduced binding of VPS35 with WASH-complex member FAM21, and robustly elevated phosphorylation of the LRRK2 kinase substrate Rab10. In cultured cortical neurons, the mutation results in increased endosomal recycling protein density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate release, and GluA1 surface expression. LRRK2 kinase inhibition exerted genotype-specific effects on GluA1 surface expression, but did not impact glutamate release phenotypes. These results improve our understanding of the early effects of the D620N mutation on cellular functions that are specific to neurons. These observations provide candidate pathophysiological pathways that may drive eventual transition to late-stage parkinsonism in VPS35 families, and support a synaptopathy model of neurodegeneration.

neuroscience↗

bioRxiv2020

Chronic lithium treatment alters the excitatory/inhibitory balance of synaptic networks and reduces mGluR5-PKC signaling

Bipolar disorder (BD) is characterized by cyclical alternations between mania and depression, often comorbid with psychosis, and suicide. The mood stabilizer lithium, compared to other medications, is the most efficient treatment for prevention of manic and depressive episodes. The pathophysiology of BD, and lithiums mode of action, are yet to be fully understood. Evidence suggests a change in the balance of excitatory/inhibitory activity, favouring excitation in BD. Here, we sought to establish a holistic appreciation of the neuronal consequences of lithium exposure in mouse cortical neurons and identify underlying mechanisms. We found that chronic (but not acute) lithium treatment significantly reduced intracellular calcium flux, specifically through the activation of the metabotropic glutamatergic receptor mGluR5. This was associated with altered phosphorylation of PKC and GSK3 kinases, reduced neuronal excitability, and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory/inhibitory balance in the network toward inhibition. Together, the results revealed how lithium dampens neuronal excitability and glutamatergic network activity, which are predicted to be overactive in the manic phase of BD. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium, but with reduced toxicity.

neuroscience↗