Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition

Area of Science:

• Neuroscience
• Pharmacology
• Neurobiology

Background:

• N-methyl-D-aspartate receptors (NMDARs) are crucial for neuronal function and dysfunction, particularly in the prefrontal cortex (PFC), a region implicated in neuropsychiatric disorders.
• While AT₁ receptor activation enhances NMDAR activity, alternative angiotensin pathways, potentially via AT₄ receptors (AT4Rs), may inhibit NMDAR function.
• Angiotensin IV (Ang IV) and its analogs show promise in improving cognitive deficits in animal models.

Purpose of the Study:

• To determine the cell-type specific localization of AT4 receptor (AT4R), which is identical to insulin-regulated aminopeptidase (IRAP).
• To investigate the modulatory effects of Ang IV on NMDAR function in layer V pyramidal neurons of the rat PFC.

Main Methods:

• Utilized immunohistochemistry to map AT4R/IRAP expression in the rat PFC.
• Employed whole-cell patch-clamp electrophysiology to assess the impact of Ang IV on NMDAR currents in layer V pyramidal neurons.
• Administered Ang IV and an IRAP inhibitor (LVVYP-H7) to evaluate inhibitory effects on NMDA-induced currents.

Main Results:

• AT4R/IRAP was found in pyramidal cells and GABAergic interneurons in layer V of the PFC in young and adult rats.
• Ang IV significantly inhibited NMDA-induced currents in a subset of PFC pyramidal neurons in a dose-dependent manner.
• The IRAP inhibitor LVVYP-H7 replicated Ang IV's inhibitory effect, and this inhibition persisted even after synaptic isolation.

Conclusions:

• Ang IV, acting through AT4R/IRAP, inhibits NMDAR activity in PFC layer V pyramidal neurons.
• This inhibitory mechanism offers a potential pathway for regulating cognitive functions.
• The Ang IV/IRAP pathway represents a promising pharmacological target for treating cognitive impairments and associated neuropsychiatric disorders.