The application of electrophysiological experiments in revealing that ATP regulates depression-like behaviors through the mPFC→LHb loop

The prefrontal cortex (PFC), hippocampus, and amygdala are most associated with depression, and the medial prefrontal cortex (mPFC) is the most severely damaged region in depression: neuronal structures in this region (decreased synapses, Decreased dendritic complexity) and functional changes (synaptic transmission disturbances), there is an imbalance in intracellular energy homeostasis, which can be alleviated by antidepressant treatment

ATP (adenosine triphosphate) is the basic source of cellular energy, and the level of extracellular ATP in the mPFC region of animal models of depression is reduced

The mPFC projects to multiple brain regions, among which the dorsal raphe nucleus (DRN) and the lateral stiff nucleus (LHb) are also closely related to the occurrence of depression: activation of mPFC→DRN can improve depression-like behaviors, and activation of mPFC→LHb can induce depression-like behaviors behavior

In July 2022, the journal Biological Psychiatry officially published an article by Academician Gao Tianming of Southern Medical University, revealing that ATP regulates depression-like behaviors through the mPFC→LHb loop

The neurons projecting from the mPFC to the DRN and LHb regions are almost all excitatory neurons, and about 2% are inhibitory neurons

Figure 1: Recording of postsynaptic currents in mPFC→LHb neurons

Electrophysiological experiments found that chronic stress did not affect the synaptic transmission function and neuronal excitability of neurons projecting from the mPFC region to the DRN, but significantly reduced the spontaneous inhibitory postsynaptic currents of the neurons projecting to the LHb from the mPFC region and increased neuronal excitability.

Interestingly, the inhibitory postsynaptic current of mPFC→LHb neurons was also decreased in ITPR2 knockout mice, and the excitability of neurons was increased

ATP regulates inhibitory synaptic transmission through the purinergic receptor P2rx2

ATP analogs can significantly increase inhibitory postsynaptic currents and decrease excitatory postsynaptic currents in mPFC pyramidal neurons, and specific knockout of P2rx2 on mPFC inhibitory neurons can block the effects of ATP analogs on chronic stress or chronic stress.

Figure 2: Inhibition of mPFC→LHb improves depression-like behavior

The above results confirm that mPFC→LHb neurons are overexcited in an animal model of depression.

Collectively, this paper reveals that chronic stress impairs ITPR2-dependent ATP release, causing a decrease in extracellular ATP levels, reducing purinergic receptors that activate inhibitory neurons in the mPFC region, and ultimately causing hyperexcitability of mPFC→LHb neurons specifically

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