NPP—Xu Yun's research group revealed that microalbumin-positive interneurons in the prefrontal cortex play an important role in the regulation of mood disorders in the early stage of Alzheimer's disease

Editor—Summer Leaf

Alzheimer's disease (AD) is a common neurodegenerative disease
with an insidious onset and continuous progression.
Cognitive dysfunction is one of the most characteristic features of AD, usually initially manifesting as impaired short-term memory in the preclinical phase and then progressively showing severe long-term memory decline
as the disease progresses.
In addition, there is increasing evidence that depression is closely related to AD, and patients with a depressive-like phenotype are often observed in preclinical AD [1], but whether depressive symptoms are a risk factor for AD The early characteristics of AD are currently controversial
.
The prefrontal cortex (PFC) is a brain region closely related to emotional and cognitive function, and PFC dysfunction is involved in the progression of
AD.
However, whether the internal PFC microloop in the early stages of AD development is damaged and the mechanism by which it is damaged is unclear
.

The balance between excitatory and inhibitory networks within the brain (E/I balance) is considered a prerequisite for
normal physiological function in the brain.
Current research suggests that the instability of synaptic input due to glutamatergic and γ-aminobutyric acid (GABA)ergic (GABA)ergic input, i.
e.
E/I imbalance, is an important cause of AD brain dysfunction [2]
。 Vigalbumin-positive interneurons (PV+ INs) account for about 40% of GABAERGIC interneurons in the cerebral cortex, PV⁺ INs The firing of pyramidal neurons is directly controlled by synaptic projection to pyramidal neurons, thereby regulating E/I balance within brain regions and excitatory projection to downstream brain regions [3]
.
But PFC in GABA can INs, especially PV+ INs in AD The role of early emotional and cognitive dysfunction remains unclear
.

On October 13, 2022, Professor Xu Yun's team from the Drum Tower Hospital affiliated to Nanjing University School of Medicine was at Neuropsychopharmacology A report titled "Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in," was published in NPP Alzheimer's disease" research paper, presenting PFC brain regions PV⁺ INs in AD Early mood disorders play an important role
in the regulation.
Dr.
Shu Shu and PhD student Siyi Xu are the co-first authors of the paper, and Professor Xu Yun is the corresponding author
of the paper.
In this study, the authors found that impaired excitability and quantity of PV⁺ INs in early PFCs in AD led to the development of PFCs GABA transmission defects, E/I imbalance and microloop damage, resulting in early short-term working memory impairment and depression-like behavior in AD, can effectively improve PV⁺ INs activity Early cognitive
and emotional impairment in AD.

The study used 9-11-week-old APP/PS1 mice as early AD model mice (hereinafter referred to as APP mice).

In behavioral testing, the authors found that compared with littermate control mice, the percentage of spontaneous alternation of APP mice entering each arm in the Y maze was significantly reduced, the nesting score in the nesting experiment was significantly reduced, the immobility time in the hanging tail experiment was significantly increased, and the percentage of sugar water intake in the sugar water preference experiment was significantly reduced (Figure 1A-G).

The above results show that early AD mice exhibit working memory impairment and depressive-like behavior
.
Subsequently, the authors detected the local field potential (LFP) of the PFC brain region as APP mice moved through the Y maze by in vivo multichannel recording ) and pyramidal neuron spike emission levels (Figure 1H-J).

The experimental results showed that the LFP power and spike emission rate of PFC brain region were significantly reduced when wild-lit-term control mice entered the central region compared with those located in the arm region (Figure 1K).
, L, N-P), I.
E.
, THE PRESENCE OF THE NECESSARY EXCITATORY SILENCING IN THE BRAIN REGION WHEN NORMAL CONTROL MICE CHOOSE TO ENTER THE NEXT ARM.

However, when APP mice were selected in the central region of the Y maze, the power of the PFC brain region LFP was high There was no significant difference in spike emission frequency from in the arm region (Figure 1K, M, N-P).

The above results show that the necessity of cerebral neuronal activity in PFC brain and brain regions of early AD mice is impaired
during short-term memory tasks.

Fig.
1 Early AD mice exhibit short-term memory impairment and depression-like behavior and PFC brain regions are impaired with the
necessary excitatory silence during short-term working memory tasks.

(Source: Shu Shu, et al.
, NPP, 2022).

Subsequently, the authors measured the level of spike release from pyramidal neurons in the PFC brain region as the mice moved freely within their feeding cages (Figure 2A-C).

The results showed that the firing frequency of pyramidal neurons in PFCs in APP mice increased significantly compared with the control
.
Subsequently, the authors performed electrophysiological verification on in vitro PFC brain slices (Figure 2D-K).

The results showed a significant increase in the excitability level of the pyramidal neuron network in layer II/III of PFC in APP mice compared to littermate control mice (Figure 2D-H ), while the intrinsic excitability did not change significantly (Figure 2I-L).

In addition, the authors responded to the level of E/I equilibrium in
PFC brain regions by detecting eEPSCs and eIPSCs and calculating amplitude ratios.
The experimental results showed that the E/I ratio of APP mice was increased compared to littermate control mice (Figures 2M and N).

。 These results showed that the E/I balance of PFC brain regions in early AD mice was disturbed, and the excitability of pyramidal neuronal networks increased significantly while the inherent excitability did not change
significantly.

Fig.
2 The excitability of pyramidal neuronal networks in PFC brain regions of mice in early AD and the E/I balance of PFC brain regions are disturbed.

(Source: Shu Shu, et al.
, NPP, 2022).

Since this E/I imbalance may be due to increased excitatory input, decreased inhibitory input, or both, the authors examined
excitatory and inhibitory transmitter transport in APP mice, respectively.
The results showed that the frequency and amplitude of tiny excitatory postsynaptic currents (mEPSCs) in PFC pyramidal neurons of APP mice and control littermates were similar (Figure 3A-D).
, indicating that PFC glutamatergic transport did not change significantly; However, the frequency of micro-inhibitory postsynaptic currents (mIPSCs) was significantly reduced, and the amplitude did not change significantly (Figure 4A-D).

Consistent with this, the paired pulse ratio (PPR) was significantly increased in the APP mouse group (Figures 4E and F), indicating a decrease in presynaptic GABA transmitter release
。 In addition, the authors collected mouse PFC interstitial fluid samples by microdialysis and measured glutamate and GABA concentrations (Figure 4G).

The results showed that GABA release levels in PFCs in APP mice were significantly reduced but glutamate release levels did not change significantly (Figure 4H and I), i.
e.
consistent
with electrophysiological results.
The above evidence suggests that GABA transmitter delivery in the brain region of PFC in early AD mice is significantly impaired
.

Fig.
3 Glutamatergic transmitter transmission is normal
in PFC in mice in early AD.

(Source: Shu Shu, et al.
, NPP, 2022).

Fig.
4 GABA transmitter delivery in the PFC brain region of early AD mice is reduced
.

(Source: Shu Shu, et al.
, NPP, 2022).

Previous studies have shown that the inhibitory synaptic ends of GABAergic INs release GABA onto the postsynaptic membrane of pyramidal neurons, GABAergic INs The absence of GABA will result in a decrease in GABA delivery [4].

Somatostatin-positive interneurons (SOM+ INs) and PV⁺ INs are the two most important types of INs for PFCs [5]
。 Therefore, the authors detected whether the number of these two types of INs in PFCs had changed
by immunofluorescence staining.
The results showed that the number of PV+ INs in PFCs in APP mice was significantly reduced, while SOM⁺ INs were reduced No significant changes occurred (Figures 5A-F).

The authors then performed in vitro electrophysiological testing of PV⁺ INs in the PFC brain region (Figure 5G-K).

The experimental results showed that the input resistance of APP mice and littermate control mice was similar (Figure 5G), but the resting membrane potential (RMP) and action potential ( AP) issuance frequency is significantly reduced (Figure 5H and K), inducing AP The threshold for input current is significantly higher (Figure 5J).

These results indicate that the number and activity of PV⁺ INs in PFCs in early AD mice are reduced
.

Fig.
5 The number and activity of PV⁺ INs in PFC brain regions of early AD mice were reduced
.

(Source: Shu Shu, et al.
, NPP, 2022).

To investigate whether a decrease in the number and activity of PV⁺ INs in the PFC brain region is the key to short-term memory deficits and depression-like behaviors in APP mice, the authors used optogenetics and chemogenetics to determine AD The PV⁺ INs remaining in mouse PFCs were separately subjected to active intervention and their effects
on the mouse behavioral phenotype were observed.
Behavioral results showed that optogenetic or chemogenetic activation of PV⁺ INs in PFCs was effective in rescuing working memory impairment and depression-like behavior in AD mice (Fig 6）
。 The above results show that increasing the activity of PV⁺ INs in PFC can effectively rescue short-term spatial memory impairment in early AD mice and improve depression-like behavior
in mice.

Fig.
6 Increasing PV⁺ INs activity through optogenetics or chemogenetics can save short-term spatial memory and improve depression-like behavior
in AD mice.

(Source: Shu Shu, et al.
, NPP, 2022).