Parvalbumin-expressing (PV1) interneurons play a key role in the maturation and synchronization of cortical circuitry and alterations in these inhibitory neurons, especially in the medial prefrontal cortex (mPFC), have been found in different psychiatric disorders. The formation of perineuronal nets (PNNs) around many of these interneurons at the end of the critical periods reduces their plasticity and sets their connectivity. Consequently, the presence of PNNs must have an important impact on the synaptic input and the physiology of PV1 cells. In the present study, we have found that in adult male mice, prefrontocortical PV1 cells surrounded by PNNs show higher density of perisomatic excitatory and inhibitory puncta, longer axonal initial segments (AISs), and higher PV expression when compared with PV1 cells lacking PNNs. In order to better understand the impact of PNNs on the connectivity and physiology of PV1 interneurons in the mPFC, we have digested enzymatically these structures and have found a decrease in the density of inhibitory puncta on their perisomatic region but not on the PV1 perisomatic puncta on pyramidal neurons. Moreover, extracellular recordings show that the digestion of PNNs induces a decrease in c activity, an oscillation dependent on PV1 cells, in the mPFC of anesthetized mice. Our results suggest that the presence of PNNs enwrapping PV1 cells regulates their inhibitory input and has a potent influence on their activity. These results may be relevant for psychiatric research, given the alterations in PNNs, PV1 interneurons and their physiology described in different mental disorders.

The E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is activated by the fizzy-related protein homolog/CDC20-like protein 1 (cdh1) in post-mitotic neurons. Growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases. Here we show in neurons that oligomers of amyloid beta (Aβ), a peptide related to Alzheimer’s disease, cause proteasome-dependent degradation of cdh1. This leads to a subsequent increase in glutaminase (a degradation target of APC/C-Cdh1), which causes an elevation of glutamate levels and further intraneuronal Ca2+ dysregulation, resulting in neuronal apoptosis. Glutaminase inhibition prevents glutamate excitotoxicity and apoptosis in Aβ treated neurons. Furthermore, glutamate also decreases cdh1 and leads to accumulation of glutaminase, suggesting that there may be a positive feedback loop of cdh1 inactivation. We confirmed the main findings in vivo using microinjection of either Aβ or glutamate in the CA1 region of the rat hippocampus. We show here for the first time in vivo that both Aβ and glutamate cause nuclear exclusion of cdh1 and an increase in glutaminase. These results show that maintaining normal APC/C-Cdh1 activity may be a useful target in Alzheimer’s disease treatment.

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In recent years, a body of evidence has shown that the nucleus incertus (NI), in the dorsal tegmental pons, is a key node of the brainstem circuitry involved in hippocampal theta rhythmicity. Ascending reticular brainstem system activation evokes hippocampal theta rhythm with coupled neuronal activity in the NI. In a recent paper, we showed three populations of neurons in the NI with differential firing during hippocampal theta activation. The objective of this work was to better evaluate the causal relationship between the activity of NI neurons and the hippocampus during theta activation in order to further understand the role of the NI in the theta network. A Granger causality analysis was run to determine whether hippocampal theta activity with sensory-evoked theta depends on the neuronal activity of the NI, or vice versa. The analysis showed causal interdependence between the NI and the hippocampus during theta activity, whose directional flow depended on the different neuronal assemblies of the NI. Whereas type I and II NI neurons mainly acted as receptors of hippocampal information, type III neuronal activity was the predominant source of flow between the NI and the hippocampus in theta states. We further determined that the electrical activation of the NI was able to reset hippocampal waves with enhanced theta-band power, depending on the septal area. Collectively, these data suggest that hippocampal theta oscillations after sensory activation show dependence on NI neuron activity, which could play a key role in establishing optimal conditions for memory encoding.