Heart slice Model
The long QT syndrome (LQTS) is characterized by the appearance of long QT intervals in the electrocardiogram.
is accomplished by atypical ventricular tachycardia like torsade de pointes and thus results in a high risk of sudden
cardiac death. Therefore, the evaluation of a QT prolongation due to the action of new compounds plays an essential role
in pharmacological development of new drugs and in safety pharmacology. Beside the common in vivo measurements of
animal ECG and in vitro assays like the Langendorff heart model or the patch clamp analysis of herg channels expressed
in mammalian cell lines the new technique of isolated living heart slices was developed during the last years. Our results
demonstrate that standardized heart slices with normal physiology and pharmacology can be prepared from
nearly any adult laboratory animal (mouse, rat, guinea pig, etc.) and even from human biopsy material.
Physiological parameters including action potential duration (APD) can be measured over up to 30 hours with
the Synchroslice multiple slice evaluation system in up to 4 heart slices simultaneously. Different test procedures
can be performed including extracellular recording of stimulus induced cardiac field potentials or intracellular recordings
from single cardiac myocytes. Many different parameters, e.g. action potentials duration, amplitude, latency, transmural
differences, refractory periods, etc. are analyzed automatically.
Long-term potentiation in the Hippocampus
The mammalian hippocampus is a key structure for learning and memory. It is generally assumed that the formation
of new memory contents is accompanied by long-term changes in synaptic transmission in hippocampal neurons.
At the cellular level, long-term synaptic plasticity can be observed as an increased efficacy in synaptic transmission
leading to enhanced postsynaptic responses of both intracellularly and extracellularly recorded neuronal activity.
Because it is stable over many hours even in various in vitro preparations, his phenomenon has been termed long-term potentiation (LTP).
Experimentally, LTP can be easily induced in hippocampal neurons by applying specific stimulation
patterns to intrinsic afferent fibers. Since LTP is regarded as a cellular analogue to memory formation
drugs that influence LTP are regarded as potentially interfering with normal CNS function. Thus,
drug effects on induction and maintenance of hippocampal LTP are widely used for screening purposes
in neuropharmacology.
One of the most frequently used model for LTP is the hippocampal CA3 to CA1 projection that can be
easily accessed by extracellular recording techniques. In this model, electrical stimulation of CA3 afferents
to CA1 pyramidal cells, the Schaffer collaterals, by various temporal patterns robustly induces LTP.
Using the SYNCHROSCLICE, recordings from multiple hippocampal slices can be done simultaneously.
This allows a direct comparison of effects either of different drugs, or of a single drug at different concentrations.
It also helps to more effectively perform repeats of the same experiment in slices that are available at a limited
number like, for example, those coming from genetically modified animals.
An experimental model for epilepsy research
The development of antiepileptic drugs critically depends on a reliable experimental model that allows to test anticonvulsant effects. Epileptiform activity can be experimentally induced by a variety of methods both in vivo and in vitro, usually by either a reduction of postsynaptic inhibition or by a general increase of spontaneous activity. In vitro, the induction of epileptiform activity in hippocampal or neocortical brain slices can be achieved by an overactivation of postsynaptic NMDA receptors. Usually, NMDA receptors are blocked by Mg2+ ions and this Mg block is only released when postsynaptic neurons are activated through non-NMDA receptors. By reducing the extracellular Mg2+ concentration, epileptiform activity can be easily and reproducibly evoked and antivonvulsant effects of bath-applied compounds can be recorded with minimum experimental effort. Because the hippocampal slice preparation is a well-defined experimetnal model and the application of Mg2+-free extracellular solutions is easy, this is perfectly suited for pharmacological studies of anticonvulsant compounds on a routinely basis.
Using the SYNCHROSCLICE, recordings from multiple hippocampal slices can be done simultaneously. This allows a direct comparison of effects either of different drugs, or of a single drug at different concentrations. It also helps to more effectively perform repeats of the same experiment in slices that are available at a limited number like, for example, those coming from genetically modified animals.
Dopamine release in the striatum
Neurons in the basal ganglia, particularly in the striatum, integrate glutamatergic inputs from neocortical and thalamic sources and dopaminergic inputs from the substantia nigra. Functionally, the striatum is involved in planning and modulation of motor command pathways. However, the execution of a variety of other, cognitive functions also critically depends on undisturbed striatal signal integration. Thus, stimuli that are associated with reward, but also novel, unexpected or intense stimuli, and cues associated with such events, also strongly activate striatal neurons. Imbalance of the glutamatergic and dopaminergic inputs to the striatum has therefore been related to the pathophysiology of a number of neurological and psychological disorders, like Parkinson’s desease, schizophrenia or addictive behaviors.
The release of dopamine in the striatum has therefore become a standard target in pharmaceutical compound evaluation. Therefore, electrophysiological assays to monitor dopamine release have gained increasing interest. Acute brain slices from the mammalian striatum are a valuable model system to study compound effects on the release and postsynaptic actions of dopamine. Stimulating the nigrostriatal pathway leads to the formation of field potentials that are almost entirely mediated by dopamine release since they can be completely blocked by dopamine receptor antagonists.
Using the SYNCHROSCLICE, recordings from multiple striatal slices can be done simultaneously. This allows a direct comparison of effects either of different drugs, or of a single drug at different concentrations. It also helps to more effectively perform repeats of the same experiment in slices that are available at a limited number like, for example, those coming from genetically modified animals.
Metabotropic glutamate receptors
Metabotropic glutamate receptors (mGluRs) are expressed in many different structures of the mammalian CNS. In accordance with their widespread distribution, mGluRs are involved in many different functions, including, amongst others, motor control, spatial memory, olfactory priming, anxiety, and the perception of pain. A loss of mGluR expression can result in CNS malfunctions, like ataxia and learning deficits, and pathological activations of mGluRs have been reported to be linked to neurological disorders, like Chorea Huntington, Alzheimer’s disease, stroke, and epilepsy. Also, mGluRs may be involved in cognitive disorders and schizophrenia.
Given the multiple functional roles that mGluRs seem to serve, they are becoming an increasingly interesting target for pharmacological compounds. This emphasizes the need for reliable and easy-to-handle models in which mGluR functions and their modulation by specific compounds can be tested. One generally accepted model system to study mGluR function in vitro is the medial perforant path-dentate gyrus (MPP-DG) synapse in the hippocampus. In this system, application of the group-II mGluR agonist DCG-IV reduces postsynaptic responses in DG neurons to MPP stimulation.
Using the SYNCHROSCLICE, recordings from multiple hippocampal slices can be done simultaneously. This allows a direct comparison of effects either of different drugs, or of a single drug at different concentrations. It also helps to more effectively perform repeats of the same experiment in slices that are available at a limited number like, for example, those coming from genetically modified animals.