| 1. |
- Lindskog, Maria, et al.
(författare)
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Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation
- 2006
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 2:9, s. 1045-1060
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Forskningsöversikt (refereegranskat)abstract
- Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.
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| 2. |
- Hjorth, Johannes, et al.
(författare)
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GABAergic control of backpropagating action potentials in striatal medium spiny neurons
- 2008
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Konferensbidrag (refereegranskat)abstract
- Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites[1-3]. Increased calcium levels trigger changes in plasticity[4,5], which is important for learning and other functions[6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites[7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of these GABAergic inputs on the dendritic calcium dynamics is investigated.
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| 3. |
- Hjorth, Johannes, et al.
(författare)
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GABAergic control of dendritic calcium dynamics in striatal medium spiny neurons
- 2008
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Ingår i: Frontiers in Neuroinformatics. - : Frontiers Media SA. - 1662-5196.
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Konferensbidrag (refereegranskat)abstract
- Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites [1, 2, 3]. Increased calcium levels trigger changes in plasticity [4, 5], which is important for learning and other functions [6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites [7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of GABAergic inputs on the dendritic calcium dynamics is investigated.
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| 4. |
- Hjorth, Johannes, et al.
(författare)
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Gap Junctions between Striatal Fast-Spiking Interneurons Regulate Spiking Activity and Synchronization as a Function of Cortical Activity
- 2009
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 29:16, s. 5276-5286
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Tidskriftsartikel (refereegranskat)abstract
- Striatal fast-spiking (FS) interneurons are interconnected by gap junctions into sparsely connected networks. As demonstrated for cortical FS interneurons, these gap junctions in the striatum may cause synchronized spiking, which would increase the influence that FS neurons have on spiking by the striatal medium spiny (MS) neurons. Dysfunction of the basal ganglia is characterized by changes in synchrony or periodicity, thus gap junctions between FS interneurons may modulate synchrony and thereby influence behavior such as reward learning and motor control. To explore the roles of gap junctions on activity and spike synchronization in a striatal FS population, we built a network model of FS interneurons. Each FS connects to 30-40% of its neighbors, as found experimentally, and each FS interneuron in the network is activated by simulated corticostriatal synaptic inputs. Our simulations show that the proportion of synchronous spikes in FS networks with gap junctions increases with increased conductance of the electrical synapse; however, the synchronization effects are moderate for experimentally estimated conductances. Instead, the main tendency is that the presence of gap junctions reduces the total number of spikes generated in response to synaptic inputs in the network. The reduction in spike firing is due to shunting through the gap junctions; which is minimized or absent when the neurons receive coincident inputs. Together these findings suggest that a population of electrically coupled FS interneurons may function collectively as input detectors that are especially sensitive to synchronized synaptic inputs received from the cortex.
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| 5. |
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| 6. |
- Hjorth, Johannes, et al.
(författare)
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Synchronization Effects in Networks of Striatal Fast Spiking Interneurons - Role of Gap Junctions
- 2008
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Ingår i: ADVANCES IN COGNITIVE NEURODYNAMICS, PROCEEDINGS. - TOTOWA : HUMANA PRESS INC. - 9781402083860 ; , s. 63-66
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Konferensbidrag (refereegranskat)abstract
- Recent studies have found gap junctions between striatal fast spiking interneurons (FSN). Gap junctions between neocortical FSNs cause increased synchrony of firing in response to current injection, but the effect of gap junctions in response to synaptic input is unknown. To explore this issue, we built a network model of FSNs. Each FSN connects to 30-40% of its neighbours, as found experimentally, and each FSN in the network is activated by simulated up-state synaptic inputs. Simulation experiments show that the proportion of synchronous spikes in coupled FSNs increases with gap junction conductance. Proximal gap junctions increase the synchronization more than distal gap junctions. During up-states the synchronization effects in FSNs coupled pairwise with proximal gap junctions are small for experimentally estimated gap junction conductances; however, higher order correlations are significantly increased in larger FSN networks.
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