Inducible and Cell-Type Restricted Manipulation in the Entorhinal Cortex

The entorhinal cortex functions as the gateway to the hippocampal formation. However, its role in formation and consolidation of hippocampus-dependent memory remains relatively unexplored. In this issue of Neuron, Yasuda and Mayford report an elegant cell-type restricted inducible transgenic mouse overexpressing a mutant form of CaM kinase II selectively in superficial layers of medial entorhinal cortex and its upstream regions. These animals display a selective spatial memory deficit during the immediate posttraining period as well as during acquisition in the Morris water maze. Similar to the hippocampus, this time-limited involvement of entorhinal cortex in spatial memory processing suggests a crucial role for hippocampal-entorhinal circuitry in spatial memory formation

Lack of kainic acid-induced gamma oscillations predicts subsequent CA1 excitotoxic cell death

Gamma oscillations are a prominent feature of hippocampal network activity, but their functional role remains debated, ranging from mere epiphenomena to being crucial for information processing. Similarly, persistent gamma oscillations sometimes appear prior to epileptic discharges in patients with mesial temporal sclerosis. However, the significance of this activity in hippocampal excitotoxicity is unclear. We assessed the relationship between kainic acid (KA)-induced gamma oscillations and excitotoxicity in genetically engineered mice in which N-methyl-d-aspartic acid receptor deletion was confined to CA3 pyramidal cells. Mutants showed reduced CA3 pyramidal cell firing and augmented sharp wave–ripple activity, resulting in higher susceptibility to KA-induced seizures, and leading to strikingly selective neurodegeneration in the CA1 subfield. Interestingly, the increase in KA-induced γ-aminobutyric acid (GABA) levels, and the persistent 30–50-Hz gamma oscillations, both of which were observed in control mice prior to the first seizure discharge, were abolished in the mutants. Consequently, on subsequent days, mutants manifested prolonged epileptiform activity and massive neurodegeneration of CA1 cells, including local GABAergic neurons. Remarkably, pretreatment with the potassium channel blocker α-dendrotoxin increased GABA levels, restored gamma oscillations, and prevented CA1 degeneration in the mutants. These results demonstrate that the emergence of low-frequency gamma oscillations predicts increased resistance to KA-induced excitotoxicity, raising the possibility that gamma oscillations may have potential prognostic value in the treatment of epilepsy.National Institutes of Health (U.S.). Intramural Research ProgramNational Institutes of Health (U.S.) (Grant R01-MH078821)Japan Society for the Promotion of Scienc

GABAergic interneuron origin of schizophrenia pathophysiology

Hypofunction of N-methyl-d-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell-types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes-from molecular and physiological to behavioral-resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults-including excitotoxicity and oxidative stress-might help to explain their significant contribution to the development of schizophrenia.Fil: Nakazawa, Kazu. National Institute of Mental Health; Estados UnidosFil: Zsiros, Veronika. National Institute of Mental Health; Estados UnidosFil: Jiang, Zhihong. National Institute of Mental Health; Estados UnidosFil: Nakao, Kazuhito. National Institute of Mental Health; Estados UnidosFil: Kolata, Stefan. National Institute of Mental Health; Estados UnidosFil: Zhang, Shuqin. National Institute of Mental Health; Estados UnidosFil: Belforte, Juan Emilio. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders

Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia

Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model of schizophrenia in which NMDARs are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010). We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the parvalbumin-positive interneurons in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al, 2013). Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of parvalbumin-positive interneurons

Contribution of NMDA Receptor Hypofunction in Prefrontal and Cortical Excitatory Neurons to Schizophrenia-Like Phenotypes

<div><p>Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in <i>in situ</i> hybridization immunocytochemistry as well as the lack of NMDA currents with <i>in vitro</i> recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (<i>e.g.</i> spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.</p></div

Characteristics of sEPSCs in mPFC layer II/III pyramidal neurons.

*<p><i>p</i><0.02 between genotypes.</p>**<p><i>p</i><0.01 between genotypes. Data are mean ± s.e.m.</p

Mutants are impaired in multi-object short-term memory task.

<p><b>A.</b> In a standard novel object recognition task with 2-min delay, both Flox controls (white bar, n = 7; two-tailed t-test, *<i>p</i><0.05) and mutant mice (black bar, n = 8; two-tailed t-test, *<i>p</i><0.05) spent more time investigating the novel vs old object. <b>B.</b> Two-min after a five-object exploration trial, Flox controls (while bar, n = 19) spent more time investigating the novel objects during the test trial (two-tailed t-test, **<i>p</i><0.01), while mutant mice (black bar, n = 14) showed no difference for time spent investigating the novel vs old object (two-tailed t-test, <i>p</i> = 0.89). n.s., not significant. <b>C.</b> After a five-object exploration trial with almost no delay (<10 sec), both Flox controls (white bar, n = 8; two-tailed t-test, *<i>p</i><0.05) and mutants mice (black bar, n = 9; two-tailed t-test, *<i>p</i><0.05) spent more time investigating the novel vs old object.</p

Positive and negative-like phenotypes.

<p><b>A.</b> In the novel open field test, no difference in horizontal activity between mutant (black triangle, n = 8) mice and Flox (while square, n = 14) controls (two-way repeated measures ANOVA; <i>p</i> = 0.56). <b>B.</b> No significant difference for genotype (black for mutant (n = 9), white for Flox (n = 9)) in amphetamine-induced locomotor response (two-way repeated measures ANOVA after treatment; <i>p</i> = 0.12). <b>C.</b> No difference between mutant (black, n = 10) and Flox (white, n = 12) mice in the social recognition task (two-way repeated measures ANOVA; <i>p</i> = 0.56). <b>D.</b> In the saccharine preference test, both genotypes consumed saccharine more and no difference between mutant (black, n = 11) and Flox (white, n = 12) mice in saccharine preference (two-way ANOVA/LSD <i>post-hoc</i> test; <i>p</i> = 0.74). <b>E.</b> Mutant mice (black bar, n = 8) performed similarly to Flox controls (while bar, n = 9) in the female urine sniffing test (two-way ANOVA/LSD <i>post-hoc</i> test; <i>p</i> = 0.59). <b>F.</b> Mutant mice (n = 12) were comparable to flox controls (n = 11) in time spent in the open arm of the elevated plus maze (two-tailed t-test; <i>p</i> = 0.73).</p