Aging Decreases L-Type Calcium Channel Currents and Pacemaker Firing Fidelity in Substantia Nigra Dopamine Neurons

Branch, Sarah Y.; Sharma, Ramaswamy; Beckstead, Michael J.

doi:10.1523/jneurosci.4228-13.2014

Cited by 70 publications

(67 citation statements)

References 54 publications

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“…Ng is also known to be localized to the membrane when it is unbound to CaM (Dominguez-Gonzalez et al, 2007). It is possible Ng-α-syn binding occurs in the presence of calcium, as the studies presented here demonstrate decreased binding in PD correlates with decreased p-Ng as seen in the membrane fraction, indicating the result could be a by-product of calcium disturbances in degeneration (Branch et al, 2014). However, in DLB there is also decreased p-Ng in the membrane, but not decreased Ng-α-syn interaction compared to age-matched controls.…”

Section: Discussionmentioning

confidence: 67%

Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease

Koob

Shaked

Bender³

et al. 2014

Brain Research

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Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson’s disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson’s disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson’s disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson’s disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory.

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Section: Discussionmentioning

confidence: 67%

Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease

Koob

Shaked

Bender³

et al. 2014

Brain Research

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“…On protein level, qualtitative analyses revealed slight differences in hippocampal Cav1.3 expression pattern between age-groups, in that Cav1.3 expression intensity was higher in the dentate gyrus granular layer in middle-aged than in adult animals. Existing data on age-related changes of LTCC expression are conflicting, ranging from increased LTCC expression in the aged brain [41] to no changes [55] or decreased expression [42,43]. This discrepancy may be partly due to different methods of analysis, since Nunez-Santana and colleagues have recently shown that Cav1.2 and Cav1.3 expression in the hippocampus of 32 months old rat is reduced on the protein, but not on the mRNA level [56].…”

Section: Discussionmentioning

confidence: 99%

“…NSCs, NPCs, mature neurons), and which steps in adult neurogenesis (proliferation, cell survival, cell differentiation and fate Page 6 of 37 A c c e p t e d M a n u s c r i p t 6 determination) are affected. Further, the impact of aging on LTCC expression and functionality is still controversially discussed, with some authors reporting increased [41] and others reduced [42,43] LTCC expression levels in the hippocampus of aged animals. To what extent the presumed changes in LTCC properties in the aged hippocampus might contribute to the reduced levels of neurogenesis in aged individuals, has not been addressed so far.…”

Section: Introductionmentioning

confidence: 99%

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

et al. 2015

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L-type voltage gated Ca(2+) channels (LTCCs) are widely expressed within different brain regions including the hippocampus. The isoforms Cav1.2 and Cav1.3 have been shown to be involved in hippocampus-dependent learning and memory, cognitive functions that require proper hippocampal neurogenesis. In vitro, functional LTCCs are expressed on neuronal progenitor cells, where they promote neuronal differentiation. Expression of LTCCs on neural stem and progenitor cells within the neurogenic regions in the adult brain in vivo has not been examined so far, and a contribution of the individual isoforms Cav1.2 and Cav1.3 to adult neurogenesis remained to be clarified. To reveal the role of these channels we first evaluated the expression patterns of Cav1.2 and Cav1.3 in the hippocampal dentate gyrus and the subventricular zone (SVZ) in adult (2- and 3-month old) and middle-aged (15-month old) mice on mRNA and protein levels. We performed immunohistological analysis of hippocampal neurogenesis in adult and middle-aged Cav1.3(-/-) mice and finally addressed the importance of Cav1.3 for hippocampal function by evaluating spatial memory and depression-like behavior in adult Cav1.3(-/-) mice. Our results showed Cav1.2 and Cav1.3 expression at different stages of neuronal differentiation. While Cav1.2 was primarily restricted to mature NeuN(+) granular neurons, Cav1.3 was expressed in Nestin(+) neural stem cells and in mature NeuN(+) granular neurons. Adult and middle-aged Cav1.3(-/-) mice showed severe impairments in dentate gyrus neurogenesis, with significantly smaller dentate gyrus volume, reduced survival of newly generated cells, and reduced neuronal differentiation. Further, Cav1.3(-/-) mice showed impairment in the hippocampus dependent object location memory test, implicating Cav1.3 as an essential element for hippocampus-associated cognitive functions. Thus, modulation of LTCC activities may have a crucial impact on neurogenic responses and cognition, which should be considered for future therapeutic administration of LTCCs modulators.

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“…While originally thought to be crucial for the generation of intrinsic pacemaker activity in SN DA neurons (Nedergaard et al 1993;Mercuri et al 1994;Chan et al 2007;Puopolo et al 2007), it is now widely accepted that LTCCs are not essential for SN DA pacemaker activity generation, but are stabilizing pacemaker activity and its precision (Guzman et al 2009;Drion et al 2011;Branch et al 2014 (Platzer et al 2000;Striessnig and Koschak 2008)] by other ion channels, e.g. by functional down-regulation of inhibitory Kv1 potassium channels within minutes after DHP-mediated distortion of SN DA activity, or functional up-regulation of either hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, or of TTCCs (Cav3.1) on longer time scales (Chan et al 2007;Guzman et al 2009;Poetschke et al 2015).…”

Section: Cav13 L-type Ca 2+ Channels Stabilize and Stimulate Activitmentioning

confidence: 99%

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

Duda¹,

Pötschke²,

Liss³

2016

Journal of Neurochemistry

137

131

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Dopamine-releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age-dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement-related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a calcium-and activity-dependent manner. Their intrinsically generated and metabolically challenging activity is created and modulated by the orchestrated function of different ion channels and dopamine D2-autoreceptors. Here, we review increasing evidence that the mechanisms that control activity patterns and calcium homeostasis of SN DA neurons are not only crucial for their dopamine release within a physiological range but also modulate their mitochondrial and lysosomal activity, their metabolic stress levels, and their vulnerability to degeneration in PD. Indeed, impaired calcium homeostasis, lysosomal and mitochondrial dysfunction, and metabolic stress in SN DA neurons represent central converging trigger factors for idiopathic and familial PD. We summarize double-edged roles of ion channels, activity patterns, calcium homeostasis, and related feedback/feed-forward signaling mechanisms in SN DA neurons for maintaining and modulating their physiological function, but also for contributing to their vulnerability in PD-paradigms. We focus on the emerging roles of maintained neuronal activity and calcium homeostasis within a physiological bandwidth, and its modulation by PD-triggers, as well as on bidirectional functions of voltage-gated L-type calcium channels and

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Aging Decreases L-Type Calcium Channel Currents and Pacemaker Firing Fidelity in Substantia Nigra Dopamine Neurons

Cited by 70 publications

References 54 publications

Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease

Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

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