Dr. Smitha Karunakaran


Assistant Professor

Research Interest: Circuit mechanisms underlying dementia including Alzheimer’s Disease

Profile: Dr. Karunakaran received her degrees from Kasturba Medical College (MSc. Medical Biochemistry, 2000) and National Brain Research Centre (PhD. 2009). Her PhD was focused on the molecular mechanisms underlying the selective neuronal vulnerability in Parkinson’s Disease. She completed her postdoctoral training at the Friedrich Miescher Institute (FMI) in Basel studying the neural circuit mechanisms involved in long term memory consolidation. She joined CBR in 2017, where her laboratory now employs multidisciplinary approaches to study how early perturbation in fundamental neuronal circuits contribute to the early cognitive symptoms in Alzheimer’s disease.

Studies in our laboratory is focused on understanding the role of Locus Coeruleus (LC) in maintaining cognitive function in normal and pathological ageing, such as dementia.

Alzheimer’s disease (AD) is one of the most common cause of dementia. AD is an irreversible, progressive neurodegenerative disorder that slowly impairs memory and higher cognitive functions. In familial forms of AD subtle cognitive deficits develop <25 years before they develop dementia. Thus, understanding the early stages of disease pathogenesis is inevitable and is the need of the hour.

Recent studies have indicated that LC, a group of brainstem neurons synthesising norepinephrine is the site of earliest pathology in the progression of AD. Depletion of up to 30% of LC neurons has been reported in prodromal mild cognitive impairment (MCI) and 70% during AD severe dementia. Recent Magnetic Resonance Imaging (MRI) studies demonstrate direct correlation of poor episodic memory with smaller LC volumes and reduced function in subjects with MCI. However, there is a lack in understanding the fundamental processes that drive these changes during early stages of AD. Towards this, we would like to understand

  1. How hippocampus projecting locus coeruleus (LC) – norepinephrine system transform hippocampal network dynamics and modulate behaviour during early stages of AD?

 To address this question we use transgenic mice carrying familial AD mutations which mimic the pathological and behavioural hallmarks of the disease.  Using this mouse model we probe whether there are tractable memory deficits during the early stages of disease pathogenesis using quantitative hippocampus dependent behavioural assays. We further combine these quantitative behavioural assays with viral tracings to define anatomically distinct LC neural pathways projecting to hippocampus that can be causal in modulating memory and behaviour. Differential susceptibility of LC neurons during early stages of disease pathogenesis will be further studied both in vivo and in vitro using primary LC neuronal cultures. Using chemogenetics we will finally manipulate these differentially vulnerable LC neurons to assess their causal role in driving early behavioural deficits. The combination of these approaches enables us to delineate how neural circuit alterations influence behaviour during early AD.

  1. How does LC-Norepinephrine modulate hippocampus astrocytes during early stages of AD pathogenesis?

Astrocytes mediate the impact of LC derived norepinephrine on neuronal function. Recent studies have reported a crucial role for astrocytes in AD onset and progression. However, fully elucidating astrocyte function during early stages of AD has been difficult due to astrocyte heterogeneity and disease dynamics. We study specific developmentally derived subpopulations of astrocytes in adult mouse brain using birth dating technique, and how they are reliably coupled to vital functions based on physiological demands using different molecular assays and structural analysis. Our proof-of-principle demonstration is to sketch out differential astrocyte subpopulation susceptibility during early stages of AD.

Present lab members

Srishti Kushwaha
PhD Student

Email: srishtikushw@iisc.ac.in

 

 

Rupsa Roy Choudhury
PhD Student

Email: rupsaroy@iisc.ac.in

 

 

Former lab members:

Akankshya Nayak
Integrated MSc student, NISER, Bhubaneswar

Abhijith Shankaran
M. Sc Molecular Biology and Human Genetics, MAHE, Manipal

Ruchika Mahesh Agarwal,
MSc Medical Biotechnology, MS University, Baroda, Gujarat.

Shanice Jessica Hermon,
Integrated MSc student, NISER, Bhubaneswar.

Ruby Gupta,
Integrated MSc Life Sciences, Central University of Jharkhand, Jharkhand.

  1. Ravindranath V; SANSCOG Study Team. Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study: Study protocol. Alzheimer’s & Dementia. 2023 Jun;19:2450-2459. PMID: 36577090.
  2. Kommaddi RP, Verma A, Muniz-Terrera G, Tiwari V, Chithanathan K, Diwakar L, Gowaikar R, Karunakaran S, Malo PK, Graff-Radford NR, Day GS, Laske C, Vöglein J, Nübling G, Ikeuchi T, Kasuga K; Dominantly Inherited Alzheimer Network (DIAN); Ravindranath V. Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort. Translational Psychiatry. 2023 Apr 12;13:123. PMID: 37045867.
  3. Sundarakumar JS, Shahul Hameed SK; SANSCOG Study Team; Ravindranath V. Burden of Vitamin D, Vitamin B12 and Folic Acid Deficiencies in an Aging, Rural Indian Community. Frontiers in Public Health. 2021 Sep 3;9:707036. PMID: 34540786
  4. Karunakaran S#. Early beta adrenoceptor dependent time window for fear memory persistence in APPswe/PS1dE9 mice.Scientific Reports. 2021,11:870. PMID: 334415
  5. Karunakaran S#.Unraveling Early Signs of Navigational Impairment in APPswe/PS1dE9 Mice Using Morris Water Maze. Front Neurosci. 2020,14:568200.PMID: 33384577
    This article is part of the Research Topic Spring Hippocampal Research Conference and Beyond
  6. Barodia SK, Prabhakaran K, Karunakaran S,Mishra V, Tapias V. Editorial: Mitochondria and Endoplasmic Reticulum Dysfunction in Parkinson’s Disease. Frontiers in Neuroscience. 2019 Nov 8 :1171. PMID: 31780882
  7. Kommaddi RP, Tomar DS, Karunakaran S,Bapat D, Nanguneri S, Ray A, Schneider BL, Nair D, Ravindranath V. Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer’s Disease Mouse Model. Antioxidants & Redox Signaling. 2019 Dec 20:1321-1338. PMID: 31617375
  8. Kommaddi RP, Das D, Karunakaran S,Nanguneri S, Bapat D, Ray A, Shaw E, Bennett DA, Nair D, Ravindranath V. ABeta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer’s disease.  The Journal of Neuroscience. 2017 Dec 15: 2127-17. PMID:29246925
  9. Karunakaran S,Chowdhury A, Donato F, Quairiaux C, Michel CM, Caroni P. PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation. Nature Neuroscience. 2016 Mar;19(3):454-64. PMID:26807952.
  10. Ray A, Sehgal N, Karunakaran S,Rangarajan G, Ravindranath V. Dopaminergic toxin MPTP activates ASK1-p38 MAPK death signaling pathway through TNF-dependent thioredoxin oxidation in Parkinsonism mouse model. Free Radical Biology and Medicine. 2015 Oct; 87: 312-25. PMID: 26164633.
  11. Saeed U, Karunakaran S,Meka DP, Koumar RC, Ramakrishnan S, Joshi SD, Prakash N, Ravindranath V. Redox activated MAP kinase death signalling cascade initiated by ASK1 is not activated in female mice following MPTP – novel mechanism of neuroprotection. Neurotoxicity Research. 2009 Aug; 16(2): 116-26. PMID: 1952628
  12. Karunakaran Sand Ravindranath V. Activation of p38 MAP kinase in the substantia nigra leads to nuclear translocation of NF-kB in MPTP treated mice: Implication in Parkinson’s disease. Journal of Neurochemistry. 2009 May 11; 109(6): 1791-1799. PMID: 19457134
  13. Karunakaran S,Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, Seth P, Ravindranath V. Selective activation of p38 MAP kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in MPTP treated mice. The Journal of Neuroscience. 2008 Nov 19; 28(47): 12500-12509. PMID: 19020042
  14. Karunakaran S,Saeed U, Ramakrishnan S, Koumar RC, Ravindranath V.Constitutive expression and functional characterization of mitochondrial glutaredoxin (Grx2) in mouse and human brain. Brain Research. 2007 Dec 14; 1185:8 – 17. PMID: 17961515
  15. Karunakaran S,Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar S, Ravindranath V. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson’s disease: protection by alpha-lipoic acid. The FASEB Journal 2007 Jul; 21(9): 2226 – 36. PMID: 17369508

# Corresponding Author

Centre for Brain Research
Indian Institute of Science Campus
CV Raman Avenue
Bangalore 560012. India.

Email: smitha[at]cbr-iisc.ac.in
Telephone: Office +91 80 2293 3639