Striatum and the neurophysiology of movement

Neuroscience research related to the striatum and basal ganglia.

Friday, January 27, 2006

The nucleus accumbens

The striatum refers usually to the caudatus and putamen nuclei. These two nuclei are fused in the rat but separated in human. Some authors, however, consider the nucleus accumbens part of the striatum. And this can be very confusing. The nucleus accumbens (formally called nucleus accumbens septi, "nucleus leaning against the septum") is located underneath the caudate and putamen, and it is involved in motivational behaviour. This is why sometimes it is called the limbic striatum.

The distinction between striatum (i.e. caudate und putamen) and nucleus accumbens (also called ventral striatum) is important because these two areas are anatomically and functionally different. For example, the striatum receives dopaminergic inputs from the substantia nigra pars compacta; the nucleus accumbens from the ventral tegmental area.

Tuesday, January 17, 2006

Why do you walk to the refrigerator when you are hungry?

As hunger strikes you, the stomach ask for food, salivation starts, and you cannot think about anything but food. But, have you ever thought how comes that the nervous system tells to your legs that you need to walk and search for food?
The striatum is a structure responsible for the initiation of movements, in particular of those that produce reward. The striatum contains opioid receptors that participate in the hedonic evaluation of food. Pratt and Kelley (2005) found that an injection of a muscarinic receptor antagonist (scopolamine) into the striatum reduces the food intake. Water intake is not affected. At the same time, blockade of muscarinic receptors reduces the levels of proenkephalin.
Pratt and Kelley observed that after the muscarinic receptor blockade, the plasma levels of leptin, a satiety signal, were reduced. Contrary to what happen after a meal. So, the animal has the hunger signals, but it does not see the pleasure in eating.

Thursday, January 12, 2006

Serotonin in the striatum

Neurones fire action potentials at different rates. One way to modulate the firing rate is via the after-hyperpolarisation, which brings the membrane potential to a value away from threshold potential. Two recent reports describe modulation of the after-hyperpolarisation in striatal cholinergic neurones (Goldberg and Wilson 2005; Blomeley and Bracci, 2005). These neurones are spontaneously active in the brain slice, and they are a suitable candidate for the tonically-active neurones observed in vivo. These neurones become silent (i.e. do not fire action potentials) during the execution of movement.
Cholinergic neurones shows two types of after-hyperpolarisation. A medium-duration after-hyperpolarisation (mAHP), and a slow after-hyperpolarisation (sAHP). The mAHP is caused by an apamin-sensitive calcium activated potassium channel. This is a small conductance K channel, also found in other preparations. The sAHP is caused by an apamin-insensitive channel that needs to be identified. Golberg and Wilson (2005) show that Ca that enters through N-type calcium channels (Cav2.2, blocked by ω-conotoxin GVIA) activates the mAHP. On the other hand, Calcium that enters through L-type calcium channels (Cav1 blocked by dihydropyridine) activates the sAHP. The obvious hypothesis here is that there might be a specific molecular association between the Calcium and calcium-activated K channels.
The work by Blomeley and Bracci (2005) also investigates the striatal cholinergic interneurones to shows that both component of the after-hyperpolarisation (mAHP, and sAHP) were reduced by serotonin. This is quite strange, because serotonin is not a neurotransmitter commonly associated with the striatum. The authors point out that such a modulation probably was lost and therefore unnoticed in whole cell recordings that wash out the intracellular content. They use the perforated-patch technique instead, that preserves the modulation. The receptor that mediates this modulation is the 5-HT2 subtype. The modulation by serotonin occurs directly, and not via an interneurone. The author used TTX, that block voltage-dependent Na-channels (and therefore transmitter release), to show that the modulation still present. A problem that needs to be solved is whether serotonin modulates the after-hyperpolarisation at the level of the potassium channels or at the level of the calcium channel.
It will be interesting to see a study showing the role of serotonin in vivo. What would then be the role of serotonin on striatal function, such as reward-based learning?

Friday, January 06, 2006

α-synuclein mutants

Two recent articles report that the expression of A53T mutant of α-synuclein causes mitochondrial dysfunction (Lee et al., 2006; Smith et al., 2005). Lee and coworkers used a transgenic mice that overexpress the human A53 mutant; as Smith and coworkers used transfected cells.
α-synuclein (alias OMIM 163890, Park1, Park4) is a rather small peptide of 140 amino acids. It can binds to phospholipase D and inhibit its activity. Some researchers think that it play a role in synaptic vesicle recycling. The mutation A53T, which occur is some forms of Parkinson's disease, apparently does not produce a significant change in the tertiary structure of the protein, and it does not cause a change in the affinity for lipid surfaces either (Bussell & Eliezer, 2004). What the mutation does, however, is to increases the propensity to form agregates (Conway et al., 1998).
Lee and co-workers found that A53T induces mitochondrial degeneration and apoptosis. Damaged mitochondria appear as swollen, shrunken or vacuolated. Interestingly, they noticed that mitochondrial DNA damage, as revealed by terminal deoxynucleotidy transferase-mediated biotinylated UTP nick end labelling (TUNEL), precedes the nuclear damage. Suggesting that mitochondria may die before the cell does.
Smith and co-workers transfected PC12 (dopaminergic) cells with a vector carrying the A53T mutant. They found that the A53T mutant decreased proteosome activity, increased the reactive oxidative species (ROS) levels, and increased the activity of caspases -3, -9, and -12, indicating activation of an apoptotic pathway.


Several mice expressing α-synuclein have shown diverse phenotype, depending on the promoter that controls the α-synuclein gene.
Promoter
Phenotype
Who
platelet-driven growth factor-α (human)
  • some motor imparement
  • nonfilamentous inclusions
Masliah et al., 2000
TH no neuropathological phenotype Matsuoka et al., 2001
Thy-1 (murine) motor deficits van der Putten et al., 2000
PrP (mouse)
  • paralysis
  • α-Syn inclusions
Giasson et al., 2002
But here, the most curious thing is not that there are different results according to the promoter used. What is astonishing is that no damage to the substantia nigra has been found. α-synuclein is found mutated in some forms of Parkinson's disease, whose landmark is the degeneration of dopaminergic neurones from the substantia nigra pars compacta. A model of the disease should first reproduce this basic fact.
In any case, what we can learn from these two articles is that α-synuclein mutant may be toxic because it destroys the mitochondria.

Wednesday, January 04, 2006

Understanding Südhof

If you are tired of reading articles telling the same story, repeating or confirming established standpoints, then you need to read the recent article by the team of Südhof (2005) published in the journal Cell. The article deals with two proteins: α-synuclein, and cystein-string protein-α (CSP-α). The results shows a curious phenomenon in which one protein can rescue the deficits caused by the absence of the other.
α-synuclein is a synaptic protein that appears mutated in some hereditary forms of Parkinson disease. Although the biochemical mechanism is unknown, it has been found that α-synuclein forms proteinaceous inclusion (Lewis bodies) similar to those found in Alzheimer's disease. Recently, it was reported that α-synuclein disperses from the terminal in response to neural activity. Deleting α-synuclein from the genome apparently has no consequences (Chandra et al., 2004). Only when both α- and β-synuclein are deleted, dopamine levels decreased by 20%. So, it seems that α-synuclein is not essential for neural function.
The cystein-string protein-α is a chaperone associated with the synaptic vesicle presumably via the fatty acids attached to cysteins residues of the cystein domains (Gundersen et al., 1994). CSP-α has a DNA-J domain that mediate interactions with the heat-shock protein and cognates (Hsp70/Hsc70) chaperone ATPases. It is able to both co-assemble with Hsc70 and turn on its ATPase activity.
Südhof points out that the synaptic terminal may be very active and has a large turnover of proteins. Some of these proteins may have defects and need to be re-folded or recycled. Since the synaptic terminal is far away from the soma it may require a private repairing machinery to ensure that misfolded and defected proteins are removed. He says:

"The synaptic vesicle localization and cochaperone activity of CSPα suggest that it may function in preventing the accumulation of nonnative, potentially toxic molecules during the continuous operation of a nerve terminal."
Südhof and co-workers used overexpression of both wild type and mutant of α-synuclein to rescue the phenotype caused by the absence of CSP-α. They noticed that the CSP-α mice have levels of α-synuclein reduced by 20%. But the reduction of α-synuclein per se does not seem to be a problem, as its deletion causes no severe deficits. Interestingly, the overexpression of human, but not murine α-synuclein rescues the phenotype. In addition, the α-synuclein mutant A30T does not rescue the phenotype. This mutant cannot anchor to the membrane, suggesting that the α-synuclein must be attached to prevent neurodegeneration.
α-synuclein, then, must have another yet to be discovered function beside clogging the protein-recycling machinery of the cell.