Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT-/-) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity.

Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats / G. Targa, F. Mottarlini, B. Rizzi, D. Leo, L. Caffino, F. Fumagalli. - In: BIOMOLECULES. - ISSN 2218-273X. - 13:3(2023 Mar 11), pp. 516.1-516.14. [10.3390/biom13030516]

Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats

G. Targa
Primo
;
F. Mottarlini
Secondo
;
B. Rizzi;L. Caffino
Penultimo
;
F. Fumagalli
Ultimo
2023

Abstract

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT-/-) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity.
dopamine transporter; glutamate; prefrontal cortex; rat;
Settore BIO/14 - Farmacologia
   Assegnazione Dipartimenti di Eccellenza 2023-2027 - Dipartimento di SCIENZE FARMACOLOGICHE E BIOMOLECOLARI
   DECC23_022
   MINISTERO DELL'UNIVERSITA' E DELLA RICERCA

   Unveiling the Role of Glutamate in dopaminE traNsporTer deficiency Syndrome (URGENT)
   URGENT
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
11-mar-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/963416
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