Synaptic adhesion molecule protocadherin-γC5 mediates ß-amyloid-induced neuronal hyperactivity and cognitive deficits in Alzheimer's disease.

Neuronal hyperactivity induced by ß-amyloid (Aß) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying mechanisms are still unclear. Here, we revealed that Aß increased the expression level of synaptic adhesion molecule protocadherin-γC5 (Pcdh-γC5) in a Ca2+-dependent manner, associated with aberrant elevation of synapses in both Aß-treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh-γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh-γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh-γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh-γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh-γC5 in mediating Aß-induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis.

Synaptic Adhesion Molecule Pcdh-γC5 Mediates Synaptic Dysfunction in Alzheimer's Disease.

Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer's disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-γC5 (Pcdh-γC5), a member of clustered Pcdh-γ subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-γC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon ß-amyloid (Aß) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experiments showed that Pcdh-γC5 modulates spontaneous synaptic currents and Aß-induced synaptic alterations directly. Our results support a model in which Pcdh-γC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-γC5 expression and associated synaptic dysfunction.SIGNIFICANCE STATEMENT Synaptic dysfunction is causal for Alzheimer's disease (AD). Here, we reveal a novel pathway that contributes GABAergic synaptic dysfunction in AD mediated by protocadherin-γC5. Our study not only identifies a new mechanism mediating excitatory/inhibitory balance in AD, but may also offer a new target for potential therapeutic intervention.

Nucleus Accumbens Corticotropin-Releasing Hormone Neurons Projecting to the Bed Nucleus of the Stria Terminalis Promote Wakefulness and Positive Affective State.

The nucleus accumbens (NAc) plays an important role in various emotional and motivational behaviors that rely on heightened wakefulness. However, the neural mechanisms underlying the relationship between arousal and emotion regulation in NAc remain unclear. Here, we investigated the roles of a specific subset of inhibitory corticotropin-releasing hormone neurons in the NAc (NAcCRH) in regulating arousal and emotional behaviors in mice. We found an increased activity of NAcCRH neurons during wakefulness and rewarding stimulation. Activation of NAcCRH neurons converts NREM or REM sleep to wakefulness, while inhibition of these neurons attenuates wakefulness. Remarkably, activation of NAcCRH neurons induces a place preference response (PPR) and decreased basal anxiety level, whereas their inactivation induces a place aversion response and anxious state. NAcCRH neurons are identified as the major NAc projection neurons to the bed nucleus of the stria terminalis (BNST). Furthermore, activation of the NAcCRH-BNST pathway similarly induced wakefulness and positive emotional behaviors. Taken together, we identified a basal forebrain CRH pathway that promotes the arousal associated with positive affective states.

Nucleus accumbens neurons expressing dopamine D1 receptors modulate states of consciousness in sevoflurane anesthesia.

Although general anesthesia (GA) enables patients to undergo surgery without consciousness, the precise neural mechanisms underlying this phenomenon have yet to be identified. In addition to many studies over the past two decades implicating the thalamus, cortex, brainstem, and conventional sleep-wake circuits in GA-induced loss of consciousness (LOC), some recent studies have begun to highlight the importance of other brain areas as well. Here, we found that population activities of neurons expressing dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), a critical interface between the basal ganglia and limbic system, began to decrease before sevoflurane-induced LOC and gradually returned after recovery of consciousness (ROC). Chemogenetic activation of NAcD1R neurons delayed induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of NAcD1R neurons exerted opposite effects. Moreover, transient activation of NAcD1R neurons induced significant cortical activation and behavioral emergence during continuous steady-state GA with sevoflurane or deep anesthesia state with constant and stable burst-suppression oscillations. Taken together, our findings uncover that NAcD1R neurons modulated states of consciousness associated with sevoflurane GA and may represent an area for targeting GA-induced changes in consciousness and ameliorating related adverse effects.

Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model.

Epilepsy is one of the most common neurological disorders affecting millions of people. Due to the complicated and unclear mechanisms of epilepsy, still a significant proportion of epilepsy patients remain poorly controlled. Epilepsy is characterized by convulsive seizures that are caused by increased excitability. In this study, by using kainic acid (KA)-induced epilepsy mice, we investigated the neuronal activities and revealed the neuronal compensatory mechanisms after KA-induced toxic hyperexcitability. The results indicate that both phasic inhibition induced by enhanced inhibitory synaptic activity and tonic inhibition mediated by activated astrocytes participate in the compensatory mechanisms. Compensatory mechanisms were already found in various neuronal disorders and were considered important in protecting nervous system from toxic hyperexcitability. This study hopefully will provide valuable clues in understanding the complex neuronal mechanisms of epilepsy, and exploring potential clinical treatment of the disease.