Pathological Plasticity

Question 1

Parkinson’s Disease

Answer 1

chronic neurodegenerative disorder characterized by a selective loss of nigrostriatal dopaminergic neurons and the consequent reduction of dopamine levels in the striatum

Question 2

What are symptoms in Parkinson patients?

Answer 2

Patients have mostly physical symptoms (movement) but also some psychological

-> 4 main: Tremor, rigidity, slowing down of movements, gait disturbance

-> Psychological: sometimes anxiety and depression

Question 3

Neurological process

Answer 3

watch image

Question 4

Nigrostriatal dopamine depletion on basal ganglia circuits

Answer 4

motor systems, preventing them from becoming active at inappropriate times

• When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation
• Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement.
• Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.

Question 5

animal models of Parkinsons disease

Answer 5

• To imitate disease in animals for research on human conditions. Study from slides:
• A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity
• early PD stages are characterized by an incomplete reduction in striatal DA levels
• Here we present a model of early PD in which a partial denervation, causing mild motor deficits, selectively affects NMDA-dependent LTP but not LTD and dramatically alters NMDA receptor composition in the postsynaptic density
• DA decrease influences corticostriatal synaptic plasticity depending on the level of depletion

Question 6

6-OHDA rat model

Answer 6

• Dopaminergic denervation in rats allows for the behavioral and neuronal differential alterations
  -> fully DA denervated rats (advanced PD) vs partially DA denervated rats (early PD)
• Fully DA denervated rats have huge deficits in motor performance
• This study, in fact, represents the first demonstration that distinct degrees of DA denervation differentially affect the induction and maintenance of two distinct and opposite forms of corticostriatal synaptic plasticity.
• An incomplete nigral denervation does not affect corticostriatal LTD
• Conversely, an incomplete DA denervation dramatically alters the maintenance of LTP
  -> demonstrating a critical role of this form of synaptic plasticity in the early motor parkinsonian symptoms
• The levels of dopamine denervation differentially alter the striatal synaptic plasticity and NMDA Receptor subunit composition
• In this model of early PD, we observed mild motor symptoms:
  -> normal LTD but altered LTP associated with an increased expression of synaptic NR2A subunits.
  -> the NR2A subunit level at the synaptic site is a major player in early phases of PD and it is sensitive to distinct degrees of DA denervation
  -> Accordingly, an uncorrected composition of NMDA receptors is a key element in both motor behavior and synaptic plasticity in the early stages of PD.
• The pathophysiological picture emerging from our data shows that the strength of glutamatergic signals from the cortex to the striatum might be dynamically regulated during the progression of the disease
• In fact, bidirectional changes in corticostriatal synaptic plasticity are critically controlled by the degree of nigral denervation that influences the endogenous DA levels and the assembly of striatal NMDA receptor subunits.

Question 7

Peptide treatment to counteract causes and symptoms

Answer 7

• Rebalance of NMDA receptor subunits by TAT2A peptide normalizes synaptic plasticity and motor behavior in early PD
• rebalancing the composition of NMDA receptors at the synaptic site, by the systemic administration of a cell-permeable peptide, rescues PD symptoms to control levels and restore altered striatal plasticity providing a promising approach for innovative and early treatment of the disease

Question 8

what is the summary of studies with PD inserted rats

Answer 8

in the early stages of the disease (incomplete reduction in striatal DA levels), the low and critical DA level does not affect corticostriatal LTD (showing that this from of plasticity only requires low levels of DA).

However, it dramatically alters the maintenance of LTP which shows the critical role of this form of plasticity in the early motor Parkinson syndromes. This is associated with an increased expression of NR2A submits of the NMDA receptor. A treatment with the TAT2A peptide might be a promising therapeutical approach because it can rebalance the NMDA receptor units.