Calcium in Neuronal Homeostasis

Calcium in Neuronal Homeostasis

Calcium in Neuronal HomeostasisSatadru DeM.Phil 1st yearDepartment of NeurophysiologyNational Institute of Mental Health And Neuro SciencesBangalore1

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Neuroscience, Dale Purves 3rd edition

3Divalent Ca2+ is the most common signal transduction element in the cells, ranging from bacteria to specialised neurons;

Implicated in several physiological processes:Excitation-contraction coupling of -Skeletal muscle -Smooth muscle, and -Cardiac muscle; Endocrine signalling of peptide hormones; Bone Calcification; Vitamin D metabolism, etc;

Ca2+ regulation is a critical process in the biochemical machinery of a neuron

Maintains neural integrity and integrates diverse cellular functions;

4Acts as a pluripotent signal for many neuronal functions:

Synaptic activity; Learning and memory consolidation; Neuronal developement;

Dysregulation of Ca2+ homeostasis may lead to:

Excitotoxicity; Channelopathies; Neurodenegeration.

Calcium in Synaptic TransmissionThe signalling between neurons along a specialised site of communication called a Synapse;

Synapses can be: -Electrical - Type 1 -Chemical - Type 2 The sequence of events at a synapse during neurotransmission:

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Transmitter Release Is Triggered by Calcium Influx

Adapted from Katz and Miledi ; 1967

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Evidence that a rise in presynaptic Ca2+ concentration triggerstransmitter release from presynaptic terminals.

After Adler et. al, 19918


9Neuroscience, Dale Purves, 3rd edition;


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Neuroscience, Dale Purves, 3rd edition;Principles of Neural Science, Kandel, 5th edition


C2A domain C2B domain3 Ca2+2 Ca2+11

Neuroscience, Dale Purves, 3rd edition; Principles of Neural Science, Kandel, 5th edition; Cold Spring Harb Perspect Biol 2012;4:a011353


C2A domain C2B domain3 Ca2+2 Ca2+12

Neuroscience, Dale Purves, 3rd edition; Principles of Neural Science, Kandel, 5th edition; Cold Spring Harb Perspect Biol 2012;4:a011353

Calcium in Learning and MemoryMemory: - Implicit - Explicit

Habituation and Sensitisation

Long term potentiation explicit memory storage in hippocampus

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Calcium in Learning and Memory(contd)14

Principles of Neural Science, Kandel 5th





Calcium in Neuronal Developement17

Calcium-mediated specification of neurotransmitter phenotype

Cold Spring Harb Perspect Biol 2011;3:a004259

Calcium-mediated specification of neurotransmitter phenotype:Prior to synaptogenesis a transient and spontaneous calcium activity is recordedXenopus embryonic spinal cord cells have two types of transient spontaneous activity: (Gu et al. 1994; Spitzer et al. 1994; Gu and Spitzer 1995, 1997) -Calcium spikes -Calcium waves

18Cold Spring Harb Perspect Biol 2011;3:a004259

Calcium-mediated specification of neurotransmitter phenotype:Prior to synaptogenesis a transient and spontaneous calcium activity is recordedXenopus embryonic spinal cord cells have two types of transient spontaneous activity: (Gu et al. 1994; Spitzer et al. 1994; Gu and Spitzer 1995, 1997) -Calcium spikes -Calcium waves

How do they determine the neurotransmitter phenotype? Embryonic Xenopus neurons showed that Ca-spikes are necessary and sufficient for specific NT expression in the spinal neurons.19Cold Spring Harb Perspect Biol 2011;3:a004259

Calcium-mediated specification of neurotransmitter phenotype:Mechanism: Intracellular Ca2+ release is needed for this differentiation Seems to occur via a frequency-mediated mechanism

regulates geneexpression? Different frequency needed for each subtype?

Before synaptogenesis cells showing low spike frequency express glutamate and with a gradually increasing spike frequency expressed Ach

Cells showing high spike frequency expressed inhibitory neurotransmitters, like GABA.

20Cold Spring Harb Perspect Biol 2011;3:a004259specific frequency for specific NT?

Calcium-mediated specification of neurotransmitter phenotype:Homeostatic relation between Ca-signalling and NT expression can be established: (Borodinsky et al. 2004)

Injection of Na-channel Injection of Kir transcript transcript at 2-celled stage

global increase in Ca- decrease in Ca-spiking spiking activity

expression expression of Glu, Ach; of Glu, Ach; expression of GABA, Gly. expression of GABA, Gly.


22Cold Spring Harb Perspect Biol 2011;3:a004259tlx3 homeobox gene mediates the activity dependant fate of GABA and Glu expression(Marek et al. 2010; Cheng et al. 2004,2005)


tlx3 homeobox gene mediates the activity dependant fate of GABA and Glu expression(Marek et al. 2010; Cheng et al. 2004,2005)

Calcium and cAMP in Axonal Guidance24Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc.

Dependence of attraction versus repulsion on calcium levels; cAMP mediated directional switching;

Calcium and cAMP in Axonal Guidance25Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc.

Blocking Ca-entry can turn a attractive cue to a repellant cue (Hong et al. 2000)

Effectors of Ca-CaM complex in growth cone turning : CaMKII and Calcineurin; CaMKII attracts; CaN repels;

Baseline calcium level is important is mediating response interaction of baseline level and influx/ IC release;

When baseline level is reduced, small or large local Ca2+ increase lowers CaMKII:CaN ration and causes repulsion;

Calcium and cAMP in Axonal Guidance26Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:

Higher Ca-CaMaffinityLower Ca-CaMaffinity


Higher Ca-CaMaffinityinhibitsinhibitorinhibitor

Lower Ca-CaMaffinity


Higher Ca-CaMaffinityLower Ca-CaMaffinityinhibitshigh

inhibitorinhibitor


Higher Ca-CaMaffinityLower Ca-CaMaffinityinhibitsinhibitoractivateshigh

inhibitor x



Lower Ca-CaMaffinitylow



Lower Ca-CaMaffinitylow x

Calcium in Excitotoxicity The Brains Exciting Poisons Neurons devoid of O2 (hypoxia, cardiac arrest, injury) ATP Depolarisation Presynaptic release of Glutamate Increased postsynaptic [Ca2+] by activation of GluRs Cyclical release of Glutamate Overexcitement of neurons and enhanced influx of Na+, K+, Ca2+ Acute effect Chronic Effect

32Neuroscience, M.F.Bear 2nd edition X

Calcium in Excitotoxicity The Brains Exciting Poisons Acute effect Chronic Effect Na+ and K+ influx Opening of VGCC/NMDAR Secondary influx of Cl- and H2O Influx of EC Ca2+ and release from IC stores Cell swelling and death Ca2+ induced activation of degrading enzymes 33

Calcium in Excitotoxicity The Brains Exciting Poisons Acute effect Chronic Effect Na+ and K+ influx Opening of VGCC/NMDAR Secondary influx of Cl- and H2O Influx of EC Ca2+ and release from IC stores Cell swelling and death Ca2+ induced activation of degrading enzymes Calpain 1 degrades the cellular Phospholipase-C Calcineurin cytoskeleton and Xanthine oxidase generate ROS Apoptosis

Perioxidative degradation of membrane34

Diseases of calcium channel defect - Channelopathies

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Structure of L-type voltage gated calcium channel

Diseases in calcium channel defect - Channelopathies 10 different genes encode the 1-subunit of the P/Q type calcium channel protein (the CACNA genes); CACNA1A gene (1A-subunit) mutation on chromosome 19p13 is implicated in

Familial Hemiplegic Episodic Ataxia 2 Spinocerebellar Idiopathic Gen Migraine(FHM) (EA2) Ataxia-6(SCA6) -eralised Epilepsy

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38Ca2+

Alzheimers Disease

39Ca2+

Alzheimers DiseaseAffects tau-phosphorylation and APP processing

A oligomers form Ca2+ conducting pores and generate ROS

A impairs NMDAR signalling and no. of NMDAR

Mutant PS1/PS2 enhance Ca-release from ER stores alter synaptic activty of hippocampus

40Ca2+

Parkinsons Disease





41Ca2+

Parkinsons Disease

Dramatic reduction in Calbindin D28k mRNA in SNpc, hippocampus of PD brains

L type VGCC open for longer duration in aged neurons Ca overload

Inc. basal metabolism of SNpc and ROS generation-synuclein potentiates Ca-dyshomeostasis

DA depletion overactivates Glu projections alter of NMDAR function





42Ca2+

Huntingtons Disease

Parkinsons DiseaseDramatic reduction in Calbindin D28k mRNA in SNpc, hippocampus of PD brains








43Ca2+

MSN neurons express high levels of mGluR5 acting via IP3R

Huntingtin(Ht) binds to IP3R and sensitises itHt interferes NR2B of NMDA-R binding to PSD-95 - hypersensitivity

Ca-overload and excitotoxocity

Opening of MPTP mitochondrial deathHuntingtons Disease

Parkinsons DiseaseDramatic reduction in Calbindin D28k mRNA in SNpc, hippocampus of PD brains








44Ca2+

Amyotrophic Lateral Sclerosis

45Ca2+

Amyotrophic Lateral SclerosisSpinal MN show relative lack of parvalbumin and Calbindin D28k lost early

Express AMPA-R lacking GluR2 Ca permeability and excitotoxicity

ETC impairment (complex I and IV) and mitochondrial death

Ca overload linked to SOD1 aggregation

46Ca2+

Epilepsy





47Ca2+

Epilepsy

Neurons in the seizure focus exhibit Paroxysmal Depolarising Shift (PDS)

Sustained excitibility TCa of thalamic relay neurons

K+ accumulation and Ca-wave in gliaFeedback stimulation of GABA and rebound AP burst

Activates at hyperpolarised state - AP





48Ca2+

Schiczophrenia

EpilepsyNeurons in the seizure focus exhibit Paroxysmal Depolarising Shift (PDS)








49Ca2+

Alteration of Ca-signalling due to developmental dysfuntions of NTs

RGS4 (inhibits Gq induced Ca-release) is downregulated in temporal cortexGAP43 (absorbs free CaM and prevents Ca-binding) increases in cortex and hippocampus

Expression of CaBP decreases in cortex

NMDAR hypofunction and deficitSchiczophrenia

EpilepsyNeurons in the seizure focus exhibit Paroxysmal Depolarising Shift (PDS)








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Calcium in Neuronal Homeostasis