Inhibition of Cdk5 in PV Neurons Reactivates Experience-Dependent Plasticity in Adult Visual Cortex.

Cyclin-dependent kinase 5 (Cdk5) has been shown to play a critical role in brain development, learning, memory and neural processing in general. Cdk5 is widely distributed in many neuron types in the central nervous system, while its cell-specific role is largely unknown. Our previous study showed that Cdk5 inhibition restored ocular dominance (OD) plasticity in adulthood. In this study, we specifically knocked down Cdk5 in different types of neurons in the visual cortex and examined OD plasticity by optical imaging of intrinsic signals. Downregulation of Cdk5 in parvalbumin-expressing (PV) inhibitory neurons, but not other neurons, reactivated adult mouse visual cortical plasticity. Cdk5 knockdown in PV neurons reduced the evoked firing rate, which was accompanied by an increment in the threshold current for the generation of a single action potential (AP) and hyperpolarization of the resting membrane potential. Moreover, chemogenetic activation of PV neurons in the visual cortex can attenuate the restoration of OD plasticity by Cdk5 inhibition. Taken together, our results suggest that Cdk5 in PV interneurons may play a role in modulating the excitation and inhibition balance to control the plasticity of the visual cortex.

Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease.

Accumulation of amyloid ß (Aß) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aß interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aß-induced suppression of long term potentiation (LTP). Furthermore, specific ablation of ErbB4 in PV neurons via Cre/loxP system greatly improved spatial memory and synaptic plasticity in the hippocampus of hAPP-J20 mice. The deposition of Aß detected by 3D6 and Thioflavin S staining and the proteolytic processing of hAPP analyzed by western blotting were not affected in the hippocampus of hAPP-J20 mice by deleting ErbB4 in PV neurons. Our data suggested that ErbB4 in PV neurons mediated Aß-induced synaptic and cognitive dysfunctions without affecting Aß levels.

Distinct Spatiotemporal Response Properties of Excitatory Versus Inhibitory Neurons in the Mouse Auditory Cortex.

In the auditory system, early neural stations such as brain stem are characterized by strict tonotopy, which is used to deconstruct sounds to their basic frequencies. But higher along the auditory hierarchy, as early as primary auditory cortex (A1), tonotopy starts breaking down at local circuits. Here, we studied the response properties of both excitatory and inhibitory neurons in the auditory cortex of anesthetized mice. We used in vivo two photon-targeted cell-attached recordings from identified parvalbumin-positive neurons (PVNs) and their excitatory pyramidal neighbors (PyrNs). We show that PyrNs are locally heterogeneous as characterized by diverse best frequencies, pairwise signal correlations, and response timing. In marked contrast, neighboring PVNs exhibited homogenous response properties in pairwise signal correlations and temporal responses. The distinct physiological microarchitecture of different cell types is maintained qualitatively in response to natural sounds. Excitatory heterogeneity and inhibitory homogeneity within the same circuit suggest different roles for each population in coding natural stimuli.

PV and SST neurons in the anterior cingulate cortex regulate social disorders in adulthood induced by sensory abnormalities in childhood.

OBJECTIVE: Childhood sensory abnormalities experience has a crucial influence on the structure and function of the adult brain. The underlying mechanism of neurological function induced by childhood sensory abnormalities experience is still unclear. Our study was to investigate whether the GABAergic neurons in the anterior cingulate cortex (ACC) regulate social disorders caused by childhood sensory abnormalities experience. METHODS: We used two mouse models, complete Freund's adjuvant (CFA) injection mice and bilateral whisker trimming (BWT) mice in childhood. We applied immunofluorescence, chemogenetic and optogenetic to study the mechanism of parvalbumin (PV) neurons and somatostatin (SST) neurons in ACC in regulating social disorders induced by sensory abnormalities in childhood. RESULTS: Inflammatory pain in childhood leads to social preference disorders, while BWT in childhood leads to social novelty disorders in adult mice. Inflammatory pain and BWT in childhood caused an increase in the number of PV and SST neurons, respectively, in adult mice ACC. Inhibiting PV neurons in ACC improved social preference disorders in adult mice that experienced inflammatory pain during childhood. Inhibiting SST neurons in ACC improved social novelty disorders in adult mice that experienced BWT in childhood. CONCLUSIONS: Our study reveals that PV and SST neurons of the ACC may play a critical role in regulating social disorders induced by sensory abnormalities in childhood.

Distribution Patterns of Subgroups of Inhibitory Neurons Divided by Calbindin 1.

The inhibitory neurons in the brain play an essential role in neural network firing patterns by releasing γ-aminobutyric acid (GABA) as the neurotransmitter. In the mouse brain, based on the protein molecular markers, inhibitory neurons are usually to be divided into three non-overlapping groups: parvalbumin (PV), neuropeptide somatostatin (SST), and vasoactive intestinal peptide (VIP)-expressing neurons. Each neuronal group exhibited unique properties in molecule, electrophysiology, circuitry, and function. Calbindin 1 (Calb1), a ubiquitous calcium-binding protein, often acts as a "divider" in excitatory neuronal classification. Based on Calb1 expression, the excitatory neurons from the same brain region can be classified into two subgroups with distinct properties. Besides excitatory neurons, Calb1 also expresses in part of inhibitory neurons. But, to date, little research focused on the intersectional relationship between inhibitory neuronal subtypes and Calb1. In this study, we genetically targeted Calb1-expression (Calb1+) and Calb1-lacking (Calb1-) subgroups of PV and SST neurons throughout the mouse brain by flexibly crossing transgenic mice relying on multi-recombinant systems, and the distribution patterns and electrophysiological properties of each subgroup were further demonstrated. Thus, this study provided novel insights and strategies into inhibitory neuronal classification.

A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system.

A structural scaffold embedding brain cells and vasculature is known as extracellular matrix (ECM). The physical appearance of ECM in the central nervous system (CNS) ranges from a diffused, homogeneous, amorphous, and nearly omnipresent matrix to highly organized distinct morphologies such as basement membranes and perineuronal nets (PNNs). ECM changes its composition and organization during development, adulthood, aging, and in several CNS pathologies. This spatiotemporal dynamic nature of the ECM and PNNs brings a unique versatility to their functions spanning from neurogenesis, cell migration and differentiation, axonal growth, and pathfinding cues, etc., in the developing brain, to stabilizing synapses, neuromodulation, and being an active partner of tetrapartite synapses in the adult brain. The malleability of ECM and PNNs is governed by both intrinsic and extrinsic factors. Glial cells are among the major extrinsic factors that facilitate the remodeling of ECM and PNN, thereby acting as key regulators of diverse functions of ECM and PNN in health and diseases. In this review, we discuss recent advances in our understanding of PNNs and how glial cells are central to ECM and PNN remodeling in normal and pathological states of the CNS.

Loss of SST and PV positive interneurons in the ventral hippocampus results in anxiety-like behavior in 5xFAD mice.

Neuropsychiatric symptoms, such as anxiety and depression often appear early in patients with Alzheimer's disease (AD), and a comorbid, anxiety-like phenotype is also found in rodents with AD. However, the underlying mechanisms behind these conditions and potential therapeutic targets to treat them remain unclear. In this study, we used 5 familial AD mutations (5xFAD) mice that developed early amyloid ß-amyloid deposition and related synaptic loss and memory deficits to identify a potential mechanism behind abnormally high anxiety levels observed in these subjects. We observed anxiety-like behavior in mice that had an excitatory/inhibitory (E/I) imbalance in the ventral hippocampus (vHPC) of 5xFAD mice. Both the number of parvalbumin-positive (PV+) and somatostatin-positive (SST+) cells decreased in the ventral hippocampus of the subject 5xFAD mice, however, no reductions were observed in calretinin-positive cells. We found that selectively inhibiting vHPC pyramidal cells via hM4Di expression normalized anxiety-like behaviors and E/I balance in 5xFAD mice. Finally, we found that the ventral hippocampus SST+ or PV+ neurons were activated through selectively expressed hM3Dq, which ameliorated anxiety-like behaviors and the synaptic E/I imbalance of vCA1 in 5xFAD mice. These results determined that anxiety-like behaviors accompanied by hippocampal synaptic E/I imbalance in 5xFAD mice are due to the loss of SST+ and PV+ interneurons in the vHPC. This provides a better understanding of high anxiety levels observed in patients with early-stage AD.

Dynamics of a disinhibitory prefrontal microcircuit in controlling social competition.

Social competition plays a pivotal role in determining individuals' social status. While the dorsomedial prefrontal cortex (dmPFC) is essential in regulating social competition, it remains unclear how information is processed within its local networks. Here, by applying optogenetic and chemogenetic manipulations in a dominance tube test, we reveal that, in accordance with pyramidal (PYR) neuron activation, excitation of the vasoactive intestinal polypeptide (VIP) or inhibition of the parvalbumin (PV) interneurons induces winning. The winning behavior is associated with sequential calcium activities initiated by VIP and followed by PYR and PV neurons. Using miniature two-photon microscopic (MTPM) and optrode recordings in awake mice, we show that VIP stimulation directly leads to a two-phased activity pattern of both PYR and PV neurons-rapid suppression followed by activation. The delayed activation of PV implies an embedded feedback tuning. This disinhibitory VIP-PV-PYR motif forms the core of a dmPFC microcircuit to control social competition.

Fingolimod increases parvalbumin-positive neurons in adult mice.

In recent years, it has been shown that central nervous system agents, such as antidepressants and antiepileptic drugs, reopen a critical period in mature animals. Fingolimod, which is used for the treatment of multiple sclerosis, also restores neuroplasticity. In this study, we investigated the effects of parvalbumin (PV)-positive neurons and perineuronal nets (PNN) on fingolimod administration with respect to neuroplasticity. Fingolimod was chronically administered intraperitoneally to mature mice. PV-positive neurons and PNN in the hippocampus, prefrontal cortex, and somatosensory cortex were analyzed. An increase in PV-positive neurons was observed in the hippocampus, prefrontal cortex, and somatosensory cortex of the fingolimod-treated mice. An increase in Wisteria floribunda agglutinin-positive PNN was confirmed in mice treated with fingolimod in the somatosensory cortex only. Fingolimod increased the density of PV-positive neurons in the brains of mature mice. The results indicate that fingolimod may change the critical period in mature animals.

Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors.

BACKGROUND: Anxiety disorders are the most common psychiatric diseases, affecting 28% of people worldwide within their lifetime. The excitation-inhibition imbalance in the amygdala is thought to be an underlying pathological mechanism; however, the cellular and molecular control of amygdala excitation-inhibition balance is largely unknown. METHODS: By using mice expressing chemogenetic activator or inhibitor channel in amygdala parvalbumin (PV) neurons, Erbin mutant mice, and mice with Erbin specifically knocked down in amygdala PV neurons, we systematically investigated the role of amygdala PV neurons and Erbin expressed therein in the pathogenesis of anxiety disorders using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: In naïve mice, chemogenetic inhibition of PV neurons produced anxiogenic effects, suggesting an essential role in the regulation of anxiety. In stressed mice with anxiety, excitatory postsynaptic responses on amygdala PV neurons were selectively diminished, accompanied by a decreased expression of Erbin specifically in amygdala PV neurons. Remarkably, both Erbin mutant mice and amygdala PV-specific Erbin knockdown mice exhibited impaired excitatory postsynaptic responses on amygdala PV neurons and increased anxiety-like behaviors. Furthermore, chemogenetic activation of amygdala PV neurons normalized anxiety behaviors in amygdala PV-specific Erbin knockdown mice and stressed mice. CONCLUSIONS: Together, these results demonstrate that Erbin in PV neurons is critical for maintaining the excitation-inhibition balance in the amygdala and reveal a novel pathophysiological mechanism for anxiety disorders.

Neuregulin directed molecular mechanisms of visual cortical plasticity.

Experience-dependent critical period (CP) plasticity has been extensively studied in the visual cortex. Monocular deprivation during the CP affects ocular dominance, limits visual performance, and contributes to the pathological etiology of amblyopia. Neuregulin-1 (NRG1) signaling through its tyrosine kinase receptor ErbB4 is essential for the normal development of the nervous system and has been linked to neuropsychiatric disorders such as schizophrenia. We discovered recently that NRG1/ErbB4 signaling in PV neurons is critical for the initiation of CP visual cortical plasticity by controlling excitatory synaptic inputs onto PV neurons and thus PV-cell mediated cortical inhibition that occurs following visual deprivation. Building on this discovery, we review the existing literature of neuregulin signaling in developing and adult cortex and address the implication of NRG/ErbB4 signaling in visual cortical plasticity at the cellular and circuit levels. NRG-directed research may lead to therapeutic approaches to reactivate plasticity in the adult cortex.