Unraveling the participation of the P2Y1 receptor in striatal dysfunctions of dopamine-depleted mice: an electrophysiological approach

• Grant number: 23/06200-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 22, 2023
• End date: August 21, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Roberta Andrejew Caetano
• Supervisor: Baufreton Jerome
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Université de Bordeaux, Carreire/Victoire, France
• Associated to the scholarship: 19/24553-5 - The role of P2Y1 receptor in Parkinsons Disease, BP.DR

Abstract

The basal ganglia are a core that controls movement. Its circuitry is mainly formed by inputs from cortical and thalamic glutamatergic neurons, striatal and pallidal GABAergic neurons, and dopaminergic neurons from substantia nigra. Dopamine receptors on GABAergic neurons control their excitability, plasticity, and neurotransmitter release. Parkinsonian rodents present hypoactivity of dopamine D1 receptors and hyperactivity of dopamine D2 receptors, which promote and inhibit movement in healthy conditions, respectively. The purinergic P2Y1 receptor (P2Y1R) is preferentially activated by extracellular ADP and it can modulate glutamate and dopamine release, neuroinflammation, and synaptic plasticity. The P2Y1R has a major role in regulating astrocytes' hyperexcitability and several works indicate that astrocyte P2Y1R may control neuronal glutamatergic signaling, LTP induction, and synaptic integrity, as well as regulate glutamatergic neuron loss mediated by ionotropic NMDA receptors. Data from Roberta Andrejew's Ph. D project indicate that the P2Y1R is participating in dopaminergic neuron death and motor impairment. We found that the P2Y1R is expressed on astrocytes and not on dopaminergic neurons. Therefore, we hypothesize that P2Y1R might modulate glutamate release from cortical pre-synaptic terminals in the striatum, possibly modulating striatal astrocytes, and consequently affecting the communication of striatopallidal GABAergic neurons in dopamine-depleted animals. To evaluate this pathway, we will perform several electrophysiological recordings to assess the excitability and neurotransmitter release of cortical, striatal, and pallidal neurons in dopamine-depleted mice under P2Y1R activity modulation. We also aim to specifically target neurons from direct and indirect pathways by injecting viral constructs carrying fluorescent gene reporters, enabling their distinction. Later, we will activate neurons from the direct and indirect pathways by optogenetics to establish whether the P2Y1R is participating in striatal circuitry. At the end, we intend to establish whether the P2Y1R (1) participates in corticostriatal glutamatergic neurotransmission, and whether this is modulated by astrocytes, and (2) modulates the striatal circuitry selectively by direct or indirect pathway in the dopamine-depleted mice. (AU)