Striatal glutamatergic neurotransmission and plasticity in Parkinson’s disease and aging

Parkinson's disease (PD) is a devastating neurodegenerative disorder with aging as the main risk factor. PD is characterized by severe movement disturbances but is also associated with non-motor symptoms. Affected motor functions in PD are due to alteration in the basal ganglia circuitry as a consequence of loss of dopaminergic neurons which project to the striatum, an important part of basal ganglia. One important mechanism controlling the neuronal activity within striatum and hence motor functions and learning is synaptic plasticity. Synaptic plasticity in striatum is highly dependent on efficient interactions between two neurotransmitters, dopamine and glutamate. Long term potentiation (LTP) form of synaptic plasticity in striatum is dependent on glutamatergic neurotransmission through NMDA receptors. As a result of progressive degeneration of the dopaminergic neurons in the substantia nigra, the glutamatergic neurotransmission is altered. This alteration directly affects LTP as it has been shown in different animal models of PD that LTP is lost in striatum of PD models.

Synaptic plasticity and it’s mechanisms of induction in experimental settings has been studied extensively for over a century, especially in hippocampus. Studying plasticity in striatum has been much more complicated due to cellular heterogeneity and random distribution of different cell types within striatum. Also, how different types of plasticity in the principal projection neurons are modulated by dopamine and other modulatory neurotransmitters in striatum is not clear. Moreover, experimental settings and different protocols for induction of synaptic plasticity in striatum in both in-vivo and in-vitro conditions results in different outcomes and effects the direction of the plasticity.

This thesis aimed to study how glutamatergic neurotransmission and LTP are affected in striatum upon dopaminergic degeneration and with aging. In paper I of this thesis we investigated the difference in using different electrophysiological recording conditions in induction of LTP in dorsolateral part of striatum using same induction protocol (high frequency stimulation). Based on our results we establish that high frequency stimulation induces opposing forms of dopamine-dependent synaptic plasticity in the striatum depending on recording method. We also conclude that cell-attached and field potential recordings can be useful methods studying LTP in striatum as they do not alter the intracellular milieu of the neurons. In paper II we studied the effect of a positive allosteric modulator of NMDA receptors containing GluN2D/2C, CIQ, on synaptic plasticity and behavioral deficits in a mouse model of PD. We demonstrated that by using CIQ we can rescue the lost LTP in 6-OHDA lesion model of PD and improve forelimb-use asymmetry. As aging is the main risk factor for developing PD in Paper III we investigated the effect of aging on LTP and the effect of CIQ on LTP, because we had shown beneficial effect of this compound on LTP in a PD model. Our result demonstrates that LTP is lost in the striatum of aged mice; however this loss does not share same mechanisms as seen in PD and LTP is not rescued by CIQ.

In conclusion the findings presented in this thesis help to better understand and study the mechanisms of synaptic plasticity in striatum under in-vitro experimental procedures. Our findings also suggest that targeting GluN2D containing NMDA receptors might have potential therapeutic implications for intervention in Parkinson's disease.

List of scientific papers

I. Skiteva O, Yao N, Nouhi M and Chergui K. (2017) High frequency stimulation induces LTD of AMPA receptor-mediated postsynaptic responses and LTP of synaptically-evoked firing in the dorsolateral striatum. Neuroscience Letters 14;666:11-16.
https://doi.org/10.1016/j.neulet.2017.12.028

II. Nouhi M, Zhang X, Yao N and Chergui K. (2017) CIQ, a positive allosteric modulator of GluN2C/D-containing N-methyl-d-aspartate receptors, rescues striatal synaptic plasticity deficit in a mouse model of Parkinson’s disease. CNS Neuroscience &Therapeutics 24(2):144-153
https://doi.org/10.1111/cns.12784

III. Nouhi M, Yao N and Chergui K (2018) A positive allosteric modulator of GluN2C/D-containing NMDA receptors fails to rescue impaired striatal synaptic plasticity in aged mice. [Manuscript]