The use of thallium diethyldithiocarbamate for mapping CNS potassium metabolism and neuronal activity: Tl⁺‐redistribution, Tl⁺‐kinetics and Tl⁺‐equilibrium distribution

Abstract

J. Neurochem. (2012) 122, 106–114. Abstract The potassium (K+) analogue thallium (Tl+) can be used as a tracer for mapping neuronal activity. However, because of the poor blood–brain barrier (BBB) K+‐permeability, only minute amounts of Tl+ enter the brain after systemic injection of Tl+‐salts like thallium acetate (TlAc). We have recently shown that it is possible to overcome this limitation by injecting animals with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC), that crosses the BBB and releases Tl+ prior to neuronal or glial uptake. TlDDC can thus be used for mapping CNS K+ metabolism and neuronal activity. Here, we analyze Tl+‐kinetics in the rodent brain both experimentally and using simple mathematical models. We systemically injected animals either with TlAc or with TlDDC. Using an autometallographic method we mapped the brain Tl+‐distribution at various time points after injection. We show that the patterns and kinetics of Tl+‐redistribution in the brain are essentially the same irrespective of whether animals have been injected with TlAc or TlDDC. Data from modeling and experiments indicate that transmembrane Tl+‐fluxes in cells within the CNS in vivo equilibrate at similar rates as K+‐fluxes in vitro. This equilibration is much faster than and largely independent of the equilibration of Tl+‐fluxes across the BBB. The study provides further proof‐of‐concept for the use of TlDDC for mapping neuronal activity and CNS K+‐metabolism. A theoretical guideline is given for the use of K+‐analogues for imaging neuronal activity with general implications for the use of metal ions in neuroimaging.

Single-Cell Resolution Mapping of Neuronal Damage in Acute Focal Cerebral Ischemia Using Thallium Autometallography

“…At the cellular level, we found complex heterogeneous Tl + uptake patterns incompatible with passive diffusion of TlDDC into the tissue supporting our conclusion from previous studies that Tl + is released from TlDDC before neuronal or astrocytic uptake. 10, 11, 24 …”

“…To this end, animals should preferentially be perfused 5 to 15 minutes after Tl + injection. 11 When net transmembrane Tl + fluxes cease, differences in activity-dependent Tl + fluxes cannot be detected. For mapping spatial patterns of neuronal damage, no such limitation exists.…”

“…The rationale behind introducing longer delays between injection and ‘read-out' of the distribution was to make the protocol compatible with in vivo small animal imaging techniques like high-resolution 201 TlDDC SPECT and diffusion-weighted magnetic resonance imaging, which require certain acquisition times. For a detailed discussion and a simplified mathematical treatment of the Tl + kinetics, see Wanger et al 11 …”

“…10 We found that, at the cellular level, Tl + uptake patterns, Tl + redistribution and Tl + kinetics were essentially the same irrespective of whether animals were injected with Tl + or TlDDC. 10, 11 …”

Spatial patterns of neuronal activity in rat cerebral cortex during non-rapid eye movement sleep

“…K + -analogus like the univalent thallium ion Tl + can be used, therefore, as tracers for imaging neuronal activity (Landowne 1975 ; Goldschmidt et al 2004 ). Furthermore, we have recently shown that the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC) passes the blood–brain barrier and can be used for mapping neuronal activity with single cell resolution in freely moving, behaving rodents, with short stimulation times of 5 min (Macharadze et al 2009 , 2012 ; Goldschmidt et al 2010 ; Wanger et al 2012 ; Lison et al 2013 ; Stöber et al 2013 ).…”