Hiroshi Ueno

Parvalbumin neurons and perineuronal nets in the mouse prefrontal cortex

The prefrontal cortex (PFC) plays a key role in cognitive functions, memory, and attention. Alterations in parvalbumin interneurons (PV neurons) and perineuronal nets (PNNs) within the PFC have been implicated in schizophrenia and autism spectrum disorder pathology. However, it remains unclear why PV neurons and PNNs in the PFC are selectively impaired. Here we aimed to clarify if PV neurons and PNNs in the PFC have region-specific features. We found that PV neurons and PNNs were increased in a region-specific manner in the PFC during postnatal development. In the mature PFC, the expression of PV protein is lower than in other parts of the cortex. Furthermore, PNNs in the mature PFC are not typical lattice-like structures and do not have the major components of PNNs and tenascin-R. The present study indicates that PV neurons and PNNs have region-specific features, and our results suggest that PV neurons and PNNs have structural vulnerability within the PFC.

Region-specific impairments in parvalbumin interneurons in social isolation-reared mice

Many neuropsychiatric disorders show localized dysfunction in specific cortical regions. The mechanisms underlying such region-specific vulnerabilities are unknown. Post-mortem analyses have demonstrated a selective reduction in the expression of parvalbumin (PV) in GABAergic interneurons in the frontal rather than the sensory cortex of patients with neuropsychiatric disorders such as schizophrenia, autism spectrum disorders, and bipolar disorders. PV neurons are surrounded by perineuronal nets (PNNs), and are protected from oxidative stress. Previous studies have shown that the characteristics of PNNs are brain region-specific. Therefore, we hypothesized that PV neurons and PNNs may be targeted in region-specific lesions in the brain. Oxidative stress was induced in mice by rearing them in socially isolated conditions. We systemically examined the distribution of PV neurons and PNNs in the brains of these mice as well as a control group. Our results show that the regions frequently affected in neuropsychiatric disorders show significantly lower PV expression and a lower percentage of PV neurons surrounded by PNNs in the brains of socially isolated mice. These results indicate that PV neurons and PNNs exhibit region-specific vulnerabilities. Our findings may be useful for elucidating the mechanisms underlying region-specific disruption of the brain in neuropsychiatric disorders.

Sensory Deprivation during Early Postnatal Period Alters the Density of Interneurons in the Mouse Prefrontal Cortex

Early loss of one sensory system can cause improved function of other sensory systems. However, both the time course and neuronal mechanism of cross-modal plasticity remain elusive. Recent study using functional MRI in humans suggests a role of the prefrontal cortex (PFC) in cross-modal plasticity. Since this phenomenon is assumed to be associated with altered GABAergic inhibition in the PFC, we have tested the hypothesis that early postnatal sensory deprivation causes the changes of inhibitory neuronal circuit in different regions of the PFC of the mice. We determined the effects of sensory deprivation from birth to postnatal day 28 (P28) or P58 on the density of parvalbumin (PV), calbindin (CB), and calretinin (CR) neurons in the prelimbic, infralimbic, and dorsal anterior cingulate cortices. The density of PV and CB neurons was significantly increased in layer 5/6 (L5/6). Moreover, the density of CR neurons was higher in L2/3 in sensory deprived mice compared to intact mice. These changes were more prominent at P56 than at P28. These results suggest that long-term sensory deprivation causes the changes of intracortical inhibitory networks in the PFC and the changes of inhibitory networks in the PFC may contribute to cross-modal plasticity.

Age-dependent and region-specific alteration of parvalbumin neurons and perineuronal nets in the mouse cerebral cortex

&NA; Cognitive function declines with age. Such function depends on &ggr;‐oscillation in the frontal cortex. Pyramidal neurons, and the parvalbumin‐expressing interneurons (PV neurons) that control them, are important for the generation of &ggr;‐oscillation. The mechanism by which cognitive function declines is unclear. Perineuronal nets (PNNs) mainly surround the soma and proximal dendrites and axon segments of PV neurons in the cerebral cortex. Previous evidence indicates that PNNs inhibit neural plasticity. If this is true, an increase in the number of neurons surrounded by PNNs or in the thickness or density of the PNNs around neurons could decrease plasticity in the cortex. To determine if an aging‐related change in cortical PNNs occurs, we examined the influence of aging on PV neurons and whether Wisteria floribunda agglutinin‐positive PNNs differ depending on the cortical area. The results showed that the number of PV neurons/mm2 did not change in many areas of the cortex as mice aged. In contrast, the number of neurons in the sensory cortex surrounded by PNNs increased as mice aged. Thus, with age, PNN density increases in some cortical areas but not in others. In addition, the expression level of PV protein in PV neurons decreased with aging in the whole cortex. We suggest that decreased expression of PV protein impairs fast spiking in PV neurons. We propose that PNNs surround more neurons as age increases. This aging‐related increase in PNNs decreases plasticity in the cerebral cortex and reduces cognitive function. The first step in investigating this proposal would be to determine if PNN density increases with age. HighlightsPV neuron density remained unchanged with aging in numerous cortical areas.WFA‐positive PNN density increased with aging in the sensory cortex.The expression level of PV protein in PV neurons decreased with aging.The PV soma area was reduced with aging in numerous cortical areas.

Postnatal development of GABAergic interneurons and perineuronal nets in mouse temporal cortex subregions

In human neuropsychiatric disorders, there are functional and anatomical abnormalities of GABAergic interneurons in each temporal cortex subregion. Furthermore, accumulation of amyloid‐β is observed in the temporal cortex in the early stages of Alzheimers disease. Each subregion of the temporal cortex has an important role in coordinating the input and output of the hippocampus. When subregions of the temporal cortex are impaired, memory and learning ability decrease. GABAergic interneurons control excitatory neurons, forming the cortico‐cortical and cortico‐hippocampal networks. However, in temporal cortex subregions, details of the distribution and developmental processes of GABAergic interneurons and perineuronal nets (PNNs) have not been elucidated. Here we examined the development of GABAergic interneurons and PNNs in mouse temporal cortex subregions. Results indicate that temporal cortex GABAergic interneurons have developmental stages different to those of the primary sensory cortex. In addition, the density of PNNs in the temporal cortex is lower than that in the sensory cortex. Furthermore, we found that the Wisteria floribunda agglutinin‐reactive extracellular matrix molecule is present in the upper level of layer 1 of the temporal cortex. These results support the idea that mouse temporal cortex subregions develop differently from other cortical regions and have region‐specific characteristics after maturation. The present study results suggested that the structure of the temporal cortex is significantly different from the sensory cortex and that temporal cortex may be highly vulnerable to neuropsychiatric and neurodegenerative disorders.

Expression of aggrecan components in perineuronal nets in the mouse cerebral cortex

Highlights • In mice, WFA-positive PNNs express aggrecan in selective brain regions.• Appearance and glycosylation of aggrecan-positive PNNs is brain-region specific.• Density of AB1031-, Cat-315-, and Cat-316-positive PNNs is brain-region specific.• Localization of WFA-, AB1031-, Cat-315-, and Cat-316-positive molecules differ in PNNs.

Empathic behavior according to the state of others in mice

Empathic behavior is essential for social activities in social animals. Therefore, lack of empathy is a feature of several neuropsychiatric disorders. However, the underlying mechanisms of empathy and which animals possess it remain unclear. In this study, we investigated whether mice show empathic behavior.

Hyaluronic acid is present on specific perineuronal nets in the mouse cerebral cortex

In the central nervous system (CNS), extracellular matrix (ECM) molecules comprise more than 20% of the volume and are involved in neuronal plasticity, synaptic transmission, and differentiation. Perineuronal nets (PNNs) are ECM molecules that highly accumulate around the soma of neurons. The components of the ECM in the CNS include proteins, proteoglycans, and glycosaminoglycans. Although hyaluronic acid (HA) is considered a constituent element of PNNs, the distribution of HA in the cortex has not been clarified. To elucidate the cortical region-specific distribution of HA, we quantitatively analyzed HA binding protein (HABP)-positive PNNs in the mature mouse cerebral cortex. Our findings revealed that HABP-positive PNNs are present throughout the mouse cortex. The distribution of many HABP-positive PNNs differed from that of Wisteria floribunda agglutinin-positive PNNs. Furthermore, we observed granular-like HABP-positive PNNs in layer 1 of the cortex. These findings indicate that PNNs in the mouse cortex show region-dependent differences in composition. HABP-positive PNNs in layer 1 of the cortex may have different functions such as neuronal differentiation, proliferation, and migration unlike what has been reported for PNNs so far.

Juvenile stress induces behavioral change and affects perineuronal net formation in juvenile mice

BackgroundMany neuropsychiatric disorders develop in early life. Although the mechanisms involved have not been elucidated, it is possible that functional abnormalities of parvalbumin-positive interneurons (PV neurons) are present. Several previous studies have shown that juvenile stress is implicated in the development of neuropsychiatric disorders. We aimed to clarify the effects of juvenile stress on behavior and on the central nervous system. We investigated behavioral abnormalities of chronically-stressed mice during juvenilehood and the effect of juvenile stress on PV neurons and WFA-positive perineuronal nets (PNNs), which are associated with vulnerability and plasticity in the mouse brain.ResultsDue to juvenile stress, mice showed neurodevelopmental disorder-like behavior. Juvenile stressed mice did not show depressive-like behaviors, but on the contrary, they showed increased activity and decreased anxiety-like behavior. In the central nervous system of juvenile stressed mice, the fluorescence intensity of WFA-positive PNNs decreased, which may signify increased vulnerability.ConclusionThis study suggested that juvenile stressed mice showed behavioral abnormalities, resembling those seen in neuropsychiatric disorders, and increased brain vulnerability.

The effects of sensory deprivation on laminar specific GABAergic innervation in the mouse barrel cortex

while negative timing (EPSP follows the action potential, induces long-term depression (LTD)). In order to clarify the effect of endogenous ACh on the STDP, STDP inductionprotocol was injected during the muscarine-induced slow-EPSP elicited by repetitive stimulation. As the result, LTP induced by positive timing was facilitated under slow-EPSP treatment, and LTD induced by negative timing was abolished by action of muscarinic receptors. Furthermore, LTP was facilitated and LTD was switched to LTP in the presence of eserine, a cholinesterase inhibitor. In the meantime, STDP was suppressed by applying excess of eserine, either by slow EPSP under eserine treatment or excess application of eserine. The STDP was abolished by atropine, a muscarinic ACh receptor antagonist. Finally, the response of NMDA receptor was enhanced by eserine. These results suggest that synaptic plasticity is modulated depending on the amount of cholinergic inputs, therefore, muscarinic activation might play an important role of top-down information in hippocampal CA1 neurons. Research fund: Global COE Program at Tamagawa University, Grants in-Aid for Scientific Research 20500278 and 21120006.