RESUMO
Canonical transient receptor potential (TRPC) channels influence various neuronal functions. Using quantitative high-resolution mass spectrometry, we demonstrate that TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. In hippocampal neurons from Trpc1/Trpc4/Trpc5-triple-knockout (Trpc1/4/5-/-) mice, lacking any TRPC1-, TRPC4-, or TRPC5-containing channels, action potential-triggered excitatory postsynaptic currents (EPSCs) were significantly reduced, whereas frequency, amplitude, and kinetics of quantal miniature EPSC signaling remained unchanged. Likewise, evoked postsynaptic responses in hippocampal slice recordings and transient potentiation after tetanic stimulation were decreased. In vivo, Trpc1/4/5-/- mice displayed impaired cross-frequency coupling in hippocampal networks and deficits in spatial working memory, while spatial reference memory was unaltered. Trpc1/4/5-/- animals also exhibited deficiencies in adapting to a new challenge in a relearning task. Our results indicate the contribution of heteromultimeric channels from TRPC1, TRPC4, and TRPC5 subunits to the regulation of mechanisms underlying spatial working memory and flexible relearning by facilitating proper synaptic transmission in hippocampal neurons.
Assuntos
Hipocampo/fisiologia , Memória de Curto Prazo , Multimerização Proteica , Transmissão Sináptica , Canais de Cátion TRPC/metabolismo , Animais , Técnicas de Inativação de Genes , Hipocampo/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Knockout , Canais de Cátion TRPC/genéticaRESUMO
Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/metabolismo , Hipocampo/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hormônio Liberador de Gonadotropina/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fosforilação , RNA Mensageiro/biossíntese , Transdução de Sinais , Sinapses/genética , Sinapses/metabolismoRESUMO
The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia.
Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Ibotênico/toxicidade , Comportamento Social , Núcleos Ventrais do Tálamo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The development of the dentate gyrus is characterized by distinct phases establishing a durable stem-cell pool required for postnatal and adult neurogenesis. Here, we report that Bcl11b/Ctip2, a zinc finger transcription factor expressed in postmitotic neurons, plays a critical role during postnatal development of the dentate gyrus. Forebrain-specific ablation of Bcl11b uncovers dual phase-specific functions of Bcl11b demonstrated by feedback control of the progenitor cell compartment as well as regulation of granule cell differentiation, leading to impaired spatial learning and memory in mutants. Surprisingly, we identified Desmoplakin as a direct transcriptional target of Bcl11b. Similarly to Bcl11b, postnatal neurogenesis and granule cell differentiation are impaired in Desmoplakin mutants. Re-expression of Desmoplakin in Bcl11b mutants rescues impaired neurogenesis, suggesting Desmoplakin to be an essential downstream effector of Bcl11b in hippocampal development. Together, our data define an important novel regulatory pathway in hippocampal development, by linking transcriptional functions of Bcl11b to Desmoplakin, a molecule known to act on cell adhesion.
Assuntos
Giro Denteado/fisiologia , Neurogênese/fisiologia , Proteínas Repressoras/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Animais Recém-Nascidos , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Desmoplaquinas/fisiologia , Feminino , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Proteínas Repressoras/genética , Células-Tronco/fisiologia , Proteínas Supressoras de Tumor/genéticaRESUMO
Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites 3,4-dihydroxyphenyacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 min after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or post-traumatic stress disorder.
Assuntos
Comportamento Animal , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Corticosterona/sangue , Extinção Psicológica , Medo , Rememoração Mental , Estresse Psicológico/psicologia , Natação , Estimulação Acústica , Doença Aguda , Animais , Modelos Animais de Doenças , Genótipo , Camundongos Endogâmicos C3H , Camundongos Endogâmicos DBA , Fenótipo , Reflexo de Sobressalto , Especificidade da Espécie , Estresse Psicológico/sangue , Estresse Psicológico/genética , Fatores de TempoRESUMO
Mitochondrial defects have been shown to be associated with the pathogenesis of Parkinson's disease (PD). Yet, experience in PD research linking mitochondrial dysfunction, e.g., deregulation of oxidative phosphorylation, with neuronal degeneration and behavioral changes is rather limited. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we have investigated the potential role of mitochondria in dopaminergic neuronal cell death in the substantia nigra pars compacta by high-resolution respirometry. Mitochondrial function was correlated with the time course of disease-related motor behavior asymmetry and dopaminergic neuronal cell loss, respectively. Unilateral 6-OHDA injections (>2.5 µg/2 µl) into the median forebrain bundle induced an impairment of oxidative phosphorylation due to a decrease in complex I activity. This was indicated by increased flux control coefficient. During the period of days 2-21, a progressive decrease in respiratory control ratio of up to -58 % was observed in the lesioned compared to the non-lesioned substantia nigra of the same animals. This decrease was associated with a marked uncoupling of oxidative phosphorylation. Mitochondrial dysfunction, motor behavior asymmetry, and dopaminergic neuronal cell loss correlated with dosage (1.25-5 µg/2 µl). We conclude that high-resolution respirometry may allow the detection of distinct mitochondrial dysfunction as a suitable surrogate marker for the preclinical assessment of potential neuroprotective strategies in the 6-OHDA model of PD.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Feixe Prosencefálico Mediano/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/fisiopatologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/fisiologia , Relação Dose-Resposta a Droga , Lateralidade Funcional , Imuno-Histoquímica , Masculino , Feixe Prosencefálico Mediano/patologia , Feixe Prosencefálico Mediano/fisiopatologia , Mitocôndrias/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Fosforilação Oxidativa/efeitos dos fármacos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Hippocampal plasticity and mnemonic processing exhibit a striking time-of-day dependence and likely implicate a temporally structured replay of memory traces. Molecular mechanisms fulfilling the requirements of sensing time and capturing time-related information are coded in dynamics of so-called clock genes and their protein products, first discovered and described in the hypothalamic suprachiasmatic nucleus. Using real-time PCR and immunohistochemical analyses, we show that in wildtype mice core clock components (mPer1/PER1, mPer2/PER2, mCry1/CRY1, mCry2/CRY2, mClock/CLOCK, mBmal1/BMAL1) are expressed in neurons of all subregions of the hippocampus in a time-locked fashion over a 24-h (diurnal) day/night cycle. Temporal profiling of these transcriptional regulators reveals distinct and parallel peaks, at times when memory traces are usually formed and/or consolidated. The coordinated rhythmic expression of hippocampal clock gene expression is greatly disordered in mice deficient for the clock gene mPer1, a key player implicated in both, maintenance and adaptative plasticity of circadian clocks. Moreover, Per1-knockout animals are severely handicapped in a hippocampus-dependent long-term spatial learning paradigm. We propose that the dynamics of hippocampal clock gene expression imprint a temporal structure on memory processing and shape at the same time the efficacy of behavioral learning.
Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Hipocampo/metabolismo , Memória/fisiologia , Proteínas Circadianas Period/genética , Percepção do Tempo/fisiologia , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Relógios Biológicos/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Criptocromos/genética , Criptocromos/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipocampo/fisiopatologia , Imuno-Histoquímica , Masculino , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Proteínas Circadianas Period/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
In the neurogenic areas of the adult rodent brain, neural stem cells (NSCs) proliferate and produce new neurons throughout the lifetime. This requires a permanent pool of NSCs, the size of which needs to be tightly controlled. The gp130-associated cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) have been implicated in regulating NSC self-renewal and differentiation during embryonic development and in the adult brain. To study the relevance of the two cytokines in vivo, we analyzed precursor cell proliferation and neurogenesis in the dentate gyrus of CNTF- and LIF-deficient mouse mutants. The number of radial glia-like NSCs, proliferative activity, and generation of new neurons were all reduced in CNTF(-/-) mutants but unaltered in LIF(-/-) animals. Conditional ablation of the signal transducer and activator of transcription 3 (STAT3) gene under the control of the human glial fibrillary acidic protein promoter resulted in a reduction of neurogenesis similar to that in CNTF(-/-) mice. The size of the granule cell layer was decreased in both mutants. Treatment of neurosphere cultures prepared from adult forebrain with CNTF inhibited overall proliferative activity but increased the number of NSCs as indicated by enhanced secondary neurosphere formation and upregulated expression of stem cell markers. Knockdown of STAT3 with short interfering RNA inhibited CNTF effects on neurospheres, and knockdown of suppressor of cytokine signaling 3 (SOCS3) enhanced them. Our results provide evidence that CNTF-induced STAT3 signaling is essential for the formation and/or maintenance of the neurogenic subgranular zone in the adult dentate gyrus and suggest that CNTF is required to keep the balance between NSC self-renewal and the generation of neuronal progenitors.
Assuntos
Fator Neurotrófico Ciliar/farmacologia , Fator Neurotrófico Ciliar/fisiologia , Giro Denteado/citologia , Giro Denteado/metabolismo , Neurogênese/fisiologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fator Neurotrófico Ciliar/genética , Imuno-Histoquímica , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/fisiologia , Camundongos , Camundongos Mutantes , Neurogênese/genética , Neurônios/citologia , Fator de Transcrição STAT3/genética , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
Patients with anxiety disorders and posttraumatic stress disorder (PTSD) exhibit exaggerated fear responses and noradrenergic dysregulation. Fear-related responses to α2-adrenergic challenge were therefore studied in DxH C3H/HeJ-like recombinant inbred (C3HLRI) mice, which are a DBA/2J-congenic strain selectively bred for a high fear-sensitized startle (H-FSS). C3HLRI mice showed an enhanced acoustic startle response and immobility in the forced swim test compared to DBA/2J controls. The α2-adrenoceptor antagonist yohimbine (Yoh; 5.0 mg/kg) induced an anxiogenic and the α2-adrenoceptor agonist clonidine (Clon; 0.1 mg/kg) an anxiolytic effect in the open field (OF) in C3HLRI but not DBA/2J mice. In auditory fear-conditioning, Yoh (5.0 mg/kg)-treated C3HLRI mice showed higher freezing during fear recall and extinction learning than DBA/2J mice, and a higher ceiling for the Yoh-induced deficit in fear extinction. No strain differences were observed in exploration-related anxiety/spatial learning or the Clon-induced (0.1 mg/kg) corticosterone surge. A global analysis of the behavioral profile of the two mouse strains based on observed and expected numbers of significant behavioral outcomes indicated that C3HLRI mice showed significantly more often fear- and stress-related PTSD-like behaviors than DBA/2J controls. The analysis of the robustness of significant outcomes based on false discovery rate (FDR) thresholds confirmed significant differences for the strain-Yoh-interactions in the OF center and periphery, the Yoh-induced general extinction deficit, strain differences in conditioned fear levels, and at the dose of 5.0 mg/kg for the Yoh-induced ceiling in freezing levels among others. The current findings are consistent with previous observations showing alterations in the central noradrenergic system of C3HLRI mice (Browne et al., 2014, Stress 17:471-83). Based on their behavioral profile and response to α2-adrenergic stimulation, C3HLRI mice are a valuable genetic model for studying adrenergic mechanisms of anxiety disorders and potentially also of PTSD.
Assuntos
Estimulação Acústica/métodos , Antagonistas de Receptores Adrenérgicos alfa 2/toxicidade , Medo/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/efeitos adversos , Animais , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos DBA , Reflexo de Sobressalto/efeitos dos fármacos , Especificidade da Espécie , Ioimbina/toxicidadeRESUMO
Reductions of glutamate acid decarboxylase (GAD67) and subsequent GABA levels have been consistently observed in neuropsychiatric disorders like schizophrenia and depression, but it has remained unclear how GABAergic dysfunction contributes to different symptoms of the diseases. To address this issue, we investigated male mice haplodeficient for GAD67 (GAD67+/GFP mice), which showed a reduced social interaction, social dominance and increased immobility in the forced swim test. No differences were found in rotarod performance and sensorimotor gating. We also addressed potential effects of social deprivation, which is known, during early life, to affect GABAergic function and induces behavioral abnormalities similar to the symptoms found in psychiatric disorders. Indeed, social isolation of GAD67+/GFP mice provoked increased rearing activity in the social interaction test and hyperlocomotion on elevated plus maze. Since GABA closely interacts with the dopaminergic, serotonergic and cholinergic neurotransmitter systems, we investigated GAD67+/GFP and GAD67+/+ mice for morphological markers of the latter systems and found increased tyrosine hydroxylase (TH)-IR fiber densities in CA1 of dorsal hippocampus. By contrast, no differences in numbers and densities of TH-positive neurons of the midbrain dopamine regions, serotonin (5-HT) neurons of the raphe nuclei, or choline acetyltransferase (ChAT)-expressing neurons of basal forebrain and their respective terminal fields were observed. Our results indicate that GAD67 haplodeficiency impairs sociability and increases vulnerability to social stress, provokes depressive-like behavior and alters the catecholaminergic innervation in brain areas associated with schizophrenia. GAD67+/GFP mice may provide a useful model for studying the impact of GABAergic dysfunction as related to neuropsychiatric disorders.
Assuntos
Aminas Biogênicas/metabolismo , Encéfalo/metabolismo , Glutamato Descarboxilase/fisiologia , Comportamento Social , Isolamento Social , Animais , Comportamento Animal , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Glutamato Descarboxilase/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Reflexo de Sobressalto/fisiologia , Teste de Desempenho do Rota-Rod , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
In the present study, reciprocal embryo transfers were conducted to examine genetic and maternal effects on the baseline and fear-sensitized acoustic startle response (ASR) in the two inbred strains C3H/HeN and DBA/2JHd and the outbred strain NMRI. The largest differences in the ASR were found in untreated strains (effect size 0.6). The transfer procedure per se had a significant effect on the behavior of NMRI mice resulting in a reduction in the baseline, and an increase in the fear-sensitized ASR. In contrast, there were no significant effects of the transfer procedure in the two inbred strains. Autosomal genetic effects had a stronger impact on the amplitude of the ASR (effect sizes 0.5) than sex (effect sizes 0.06) as revealed by reciprocal embryo transfer. Nevertheless, the genetic effects on the fear-sensitized ASR were somewhat more variable and strain-dependent (effect sizes 0.1-0.2). Global maternal effects were detected after embryo transfer into NMRI mothers resulting in a larger reduction of the ASR in the offspring of DBA and NMRI donors than C3H donors (effect sizes 0.1-0.2). An additional fostering procedure was introduced to dissect uterine and postnatal maternal effects in NMRI offspring. Uterine factors changed the baseline ASR of the offspring in direction of the recipient mother strain. Surprisingly, postnatal maternal effects on the ASR were contrary to the behavior of the rearing mother. In conclusion, both genetic and prenatal/postnatal maternal factors persistently influenced the ASR of the offspring, whereas the fear-sensitized ASR was mainly influenced by genetic factors. Our study shows that uterine and postnatal maternal influences deserve more attention when determining the phenotype of genetically engineered mice at least in the first generation following embryo transfer.
Assuntos
Blastocisto/metabolismo , Transferência Embrionária/métodos , Reflexo de Sobressalto/genética , Animais , Feminino , Técnicas Genéticas , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos DBA , Modelos Biológicos , Modelos Genéticos , Reflexo Acústico/genética , Especificidade da EspécieRESUMO
The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity.
Assuntos
Anestésicos Dissociativos/farmacologia , Encéfalo/metabolismo , Ketamina/farmacologia , Fatores de Crescimento Neural/biossíntese , RNA Mensageiro/biossíntese , Receptores de Fator de Crescimento Neural/biossíntese , Anestésicos Dissociativos/administração & dosagem , Animais , Encéfalo/anatomia & histologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Ketamina/administração & dosagem , Masculino , Fatores de Crescimento Neural/genética , Ratos , Ratos Sprague-Dawley , Receptor trkA/biossíntese , Receptor trkA/genética , Receptor trkB/biossíntese , Receptor trkB/genética , Receptor trkC/biossíntese , Receptor trkC/genética , Receptores de Fator de Crescimento Neural/genética , Esquizofrenia/induzido quimicamenteRESUMO
Plasticity related gene 1 (PRG-1) is a neuron specific membrane protein located at the postsynaptic density of glutamatergic synapses. PRG-1 modulates signaling pathways of phosphorylated lipid substrates such as lysophosphatidic acid (LPA). Deletion of PRG-1 increases presynaptic glutamate release probability leading to neuronal over-excitation. However, due to its cortical expression, PRG-1 deficiency leading to increased glutamatergic transmission is supposed to also affect motor pathways. We therefore analyzed the effects of PRG-1 function on exploratory and motor behavior using homozygous PRG-1 knockout (PRG-1-/-) mice and PRG-1/LPA2-receptor double knockout (PRG-1-/-/LPA2-/-) mice in two open field settings of different size and assessing motor behavior in the Rota Rod test. PRG-1-/- mice displayed significantly longer path lengths and higher running speed in both open field conditions. In addition, PRG-1-/- mice spent significantly longer time in the larger open field and displayed rearing and self-grooming behavior. Furthermore PRG-1-/- mice displayed stereotypical behavior resembling phenotypes of psychiatric disorders in the smaller sized open field arena. Altogether, this behavior is similar to the stereotypical behavior observed in animal models for psychiatric disease of autistic spectrum disorders which reflects a disrupted balance between glutamatergic and GABAergic synapses. These differences indicate an altered excitation/inhibition balance in neuronal circuits in PRG-1-/- mice as recently shown in the somatosensory cortex [38]. In contrast, PRG-1-/-/LPA2-/- did not show significant changes in behavior in the open field suggesting that these specific alterations were abolished when the LPA2-receptor was lacking. Our findings indicate that PRG-1 deficiency led to over-excitability caused by an altered LPA/LPA2-R signaling inducing a behavioral phenotype typically observed in animal models for psychiatric disorders.
Assuntos
Proteínas de Ligação a Calmodulina/deficiência , Comportamento Exploratório/fisiologia , Hipercinese/metabolismo , Lisofosfolipídeos/metabolismo , Transtornos Mentais/metabolismo , Proteínas do Tecido Nervoso/deficiência , Receptores de Ácidos Lisofosfatídicos/metabolismo , Sinapses/metabolismo , Animais , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipercinese/genética , Hipercinese/fisiopatologia , Hipercinese/psicologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neurônios/fisiologia , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais , Córtex Somatossensorial/metabolismo , Sinapses/genéticaRESUMO
Structural and functional plasticity of synapses are critical neuronal mechanisms underlying learning and memory. While activity-dependent regulation of synaptic strength has been extensively studied, much less is known about the transcriptional control of synapse maintenance and plasticity. Hippocampal mossy fiber (MF) synapses connect dentate granule cells to CA3 pyramidal neurons and are important for spatial memory formation and consolidation. The transcription factor Bcl11b/Ctip2 is expressed in dentate granule cells and required for postnatal hippocampal development. Ablation of Bcl11b/Ctip2 in the adult hippocampus results in impaired adult neurogenesis and spatial memory. The molecular mechanisms underlying the behavioral impairment remained unclear. Here we show that selective deletion of Bcl11b/Ctip2 in the adult mouse hippocampus leads to a rapid loss of excitatory synapses in CA3 as well as reduced ultrastructural complexity of remaining mossy fiber boutons (MFBs). Moreover, a dramatic decline of long-term potentiation (LTP) of the dentate gyrus-CA3 (DG-CA3) projection is caused by adult loss of Bcl11b/Ctip2. Differential transcriptomics revealed the deregulation of genes associated with synaptic transmission in mutants. Together, our data suggest Bcl11b/Ctip2 to regulate maintenance and function of MF synapses in the adult hippocampus.
RESUMO
INTRODUCTION: The hypo-glutamatergic hypothesis of schizophrenia is based on clinical similarities between schizophrenia and phencyclidine (PCP)-induced psychosis in mentally healthy humans. Sensorimotor gating, as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), is impaired in schizophrenic patients. In animals, noncompetitive N-methyl-D: -aspartate (NMDA) antagonists such as PCP disrupt PPI in a way that resembles the defect seen in schizophrenia. In a previous study with inbred mouse strains, low PPI levels have been demonstrated in CPB-K mice possessing low levels of hippocampal NMDA receptor densities. The present study was performed to test whether the low magnitude of PPI in CPB-K mice can be reversed by the atypical antipsychotic drug clozapine (CLZ). RESULTS: Before any treatment, CPB-K mice displayed a significant (p < 0.001) lower level in PPI and a significant (p < 0.001) higher ASR when compared to BALB/cJ mice known to have high hippocampal NMDA receptor densities. Acute and subchronic effects of a 2-week treatment with CLZ at daily doses of 5 and 10 mg/kg intraperitoneally, respectively, did not reveal any significant alteration of PPI levels in CPB-K mice. Nevertheless, the examination of motor behavior during nonstimulus trials provided a positive control for the drug's effectiveness. CONCLUSION: In summary, (1) this study confirmed our working hypothesis: Lower levels of hippocampal glutamatergic receptor densities correspond to lower sensorimotor gating in CPB-K mice, and (2) acute or subchronic treatment with CLZ did not elevate low PPI levels in CPB-K mice. Thus, further experiments will concentrate on other antipsychotic drugs to prove the predictive validity of this animal model.
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Estimulação Acústica/métodos , Clozapina/farmacologia , Inibição Neural/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Análise de Variância , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Clozapina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Inibição Neural/fisiologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Reflexo de Sobressalto/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Fatores de TempoRESUMO
Spines are considered sites of synaptic plasticity in the brain and are capable of remodeling their shape and size. A molecule thathas been implicated in spine plasticity is the actin-associated protein synaptopodin. This article will review a series of studies aimed at elucidating the role of synaptopodin in the rodent brain. First, the developmental expression of synaptopodin mRNA and protein were studied; secondly, the subcellular localization of synaptopodin in hippocampal principal neurons was analyzed using confocal microscopy as well as electron microscopy and immunogold labelling; and, finally, the functional role of synaptopodin was investigated using a synaptopodin-deficient mouse. The results of these studies are: (1) synaptopodin expression byhippocampal principal neurons develops during the first postnatal weeks and increases in parallel with the maturation of spines in the hippocampus. (2) Synaptopodin is sorted to the spine compartment, where it is tightly associated with the spine apparatus, an enigmatic organelle believed to be involved in calcium storage or local protein synthesis. (3) Synaptopodin-deficient mice generated by gene targeting are viable but lack the spine apparatus organelle. These mice show deficitsin synaptic plasticity as well as impaired learning and memory. Taken together, these data implicate synaptopodin and the spine apparatus in the regulation of synaptic plasticity in the hippocampus. Future studies will be aimed at finding the molecular link between synaptopodin, the spine apparatus organelle, and synaptic plasticity.
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Hipocampo/fisiologia , Proteínas dos Microfilamentos/fisiologia , Plasticidade Neuronal/fisiologia , Medula Espinal/fisiologia , Sinapses/fisiologia , Actinas/fisiologia , Animais , Cálcio/fisiologia , Células Piramidais/fisiologia , RatosRESUMO
Neuregulins (Nrg) are a gene family that binds to tyrosine kinase receptors of the ErbB family. The protein of Nrg1 is to be involved in heart formation, migration of neurons, axonal pathfinding and synaptic function. A relation between Nrg1 and schizophrenia is assumed. Chronic impairment in schizophrenia is characterized by different positive and negative symptoms. Detectable markers of this disease in human and in animal models are activity, social behavior and sensory processing. In this study we compared heterozygous Nrg1 mutant mice in behavior and quantification of dopaminergic and serotoninergic neurons with wild type-like littermates. In the Nrg1 mutant mice the epidermal growth factor-like domain is replaced by the neomycin resistance gene. We found significant differences in locomotor and pain perception behavior. No differences were found in specific schizophrenia social interaction and prepulse inhibition behavior. The number of dopaminergic and serotoninergic neurons did not differ in the investigated regions ventral tegmental area, substantia nigra, periaqueductal grey and raphe nuclei. In conclusion, this analyzed Nrg1 mutant mice model did not serve as a complete schizophrenia model. Particular aspects of schizophrenia disease in locomotor and sensory behavior deficits could represent in this Nrg1 mutant mice. Beside several different models could Nrg1 deficiency represent an endophenotype of schizophrenia disease.
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Modelos Animais de Doenças , Neuregulina-1/genética , Esquizofrenia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Endofenótipos , Comportamento Exploratório/fisiologia , Feminino , Heterozigoto , Masculino , Camundongos Transgênicos , Atividade Motora/fisiologia , Neuregulina-1/metabolismo , Dor Nociceptiva/metabolismo , Percepção da Dor/fisiologia , Inibição Pré-Pulso/fisiologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/patologia , Comportamento SocialRESUMO
Cholinergic neuromodulation in the hippocampus controls the salience of background context memory acquired in the presence of elemental stimuli predicting an aversive reinforcement. With pharmacogenetic inhibition we here demonstrate that hilar perforant path-associated (HIPP) cells of the dentate gyrus mediate the devaluation of background context memory during Pavlovian fear conditioning. The salience adjustment is sensitive to reduction of hilar neuropeptide Y (NPY) expression via dominant negative CREB expression in HIPP cells and to acute blockage of NPY-Y1 receptors in the dentate gyrus during conditioning. We show that NPY transmission and HIPP cell activity contribute to inhibitory effects of acetylcholine in the dentate gyrus and that M1 muscarinic receptors mediate the cholinergic activation of HIPP cells as well as their control of background context salience. Our data provide evidence for a peptidergic local circuit in the dentate gyrus that mediates the cholinergic encoding of background context salience during fear memory acquisition.Intra-hippocampal circuits are essential for associating a background context with behaviorally salient stimuli and involve cholinergic modulation at SST+ interneurons. Here the authors show that the salience of the background context memory is modulated through muscarinic activation of NPY+ hilar perforant path associated interneurons and NPY signaling in the dentate gyrus.
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Condicionamento Psicológico , Giro Denteado/citologia , Memória , Neurônios/metabolismo , Neuropeptídeo Y/genética , Acetilcolina/química , Animais , Comportamento Animal , Colinérgicos/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Medo , Inativação Gênica , Genes Dominantes , Células HEK293 , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Interneurônios/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeo Y/fisiologia , Receptor Muscarínico M1/metabolismo , Receptores de Neuropeptídeo Y/metabolismoRESUMO
OBJECTIVE: The hypo-glutamatergic hypothesis of schizophrenia is not only based on the phencyclidine-(PCP)-induced psychosis in mentally healthy humans but also on studies with schizophrenic patients showing deficits in post mortem hippocampal N-methyl-d-aspartate (NMDA) receptor gene expression and deficits in prepulse inhibition. The inbred mouse strains CPB-K and BALB/cJ display considerable differences in hippocampal NMDA receptor densities. Therefore, our working hypothesis was based on the assumption that the CPB-K mouse strain, which has a lower NMDA receptor density in hippocampal CA1, might be a possible animal model for schizophrenia. For this purpose, the inbred mouse strains CPB-K and BALB/cJ were compared by using a sensorimotor gating paradigm. METHODS: Acoustic startle response (ASR) and prepulse inhibition (PPI) of the startle reflex were measured. RESULTS: CPB-K mice displayed a significantly higher ASR and a significantly lower magnitude of PPI as compared to BALB/cJ mice. The test-retest reliability was approved for PPI in both mouse strains, which was performed in repeated sessions over 13 weeks. In summary, our working hypothesis was confirmed that lower levels of hippocampal NMDA receptor densities correspond to lower sensorimotor gating in CPB-K mice. Based on this finding, further experiments using different behavioral paradigms have to be carried out to establish the CPB-K mouse strain as an animal model of schizophrenia.
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Hipocampo/fisiologia , Inibição Psicológica , Receptores de N-Metil-D-Aspartato/metabolismo , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal/fisiologia , Relação Dose-Resposta à Radiação , Hipocampo/efeitos dos fármacos , Hipocampo/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Receptores de N-Metil-D-Aspartato/genética , Reflexo de Sobressalto/efeitos dos fármacos , Reprodutibilidade dos Testes , Especificidade da EspécieRESUMO
The effects of reciprocal embryo transfers were studied on anxiety-related behavior of inbred C3H/HeN and DBA/2J mice on the elevated plus maze (EPM), and related to amygdaloid neuropeptide Y (NPY)- and parvalbumin (PARV)-immunoreactive neurons. Embryo transfer significantly reduced closed arm entries in in-stain-transferred C3H mice, and maternal factors influenced open arm entries only in interaction with genetic background and sex. In DBA/2J-mice, embryo transfer resulted in a reduced number of NPY-immunoreactive (NPY-ir) neurons, while PARV-immunoreactive (PARV-ir) cells were not affected. In C3H/HeN mice, however, in-strain embryo transfer only resulted in a reduction of the number of PARV-immunoreactive neurons. Maternal factors mainly induced changes in the number of NPY-ir neurons in the basolateral complex of the amygdala either directly or in interaction with genetic factors. In summary, in-strain embryo transfer had a minor effect on the behavior of C3H/HeN mice, and a differential influence on the numbers of amygdaloid NPY-ir and PARV-ir neurons of inbred C3H/HeN and DBA/2J mice. Maternal factors had a stronger impact on the numbers of NPY-ir neurons than PARV-ir neurons. The present results indicate that alterations in behavior and amygdala morphology induced by embryo transfer or maternal factors depend on the genetic background of the mouse strains used.