RESUMO
Norepinephrine (NE) is released in the neocortex after activation of the locus coeruleus of the brain stem in response to novel, salient, or fight-or-flight stimuli. The role of adrenergic modulation in sensory cortices is not completely understood. We investigated the possibility that NE modifies the balance of inhibition acting on 2 different γ-aminobutyric acid (GABA)ergic pathways. Using patch-clamp recordings, we found that the application of NE induces an α(1) adrenergic receptor-mediated decrease of the amplitude of inhibitory postsynaptic currents (IPSCs) evoked by stimulation of layer I (LI-eIPSCs) and a ß and α(2) receptor-mediated increase in the amplitude of IPSCs evoked by stimulation of layer II/III (LII/III-eIPSCs). Analysis of minimal stimulation IPSCs, IPSC kinetics, and sensitivity to the GABA(A) receptor subunit-selective enhancer zolpidem corroborated the functional difference between LI- and LII/III-eIPSCs, suggestive of a distal versus somatic origin of LI- and LII/III-eIPSCs, respectively. These findings suggest that NE shifts the balance between distal and somatic inhibition to the advantage of the latter. We speculate that such shift modifies the balance of sensory-specific and emotional information in the integration of neural input to the upper layers of the auditory cortex.
Assuntos
Córtex Cerebral/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Córtex Cerebral/citologia , Neurônios/citologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacosRESUMO
BACKGROUND: A neonatal ventral hippocampal lesion (NVHL) induces behavioral and physiological anomalies mimicking pathophysiological changes of schizophrenia. Because prefrontal cortical (PFC) pyramidal neurons recorded from adult NVHL rats exhibit abnormal responses to activation of the mesocortical dopaminergic (DA) system, we explored whether these changes are due to an altered DA modulation of pyramidal neurons. METHODS: Whole-cell recordings were used to examine the effects of DA and glutamate agonists on cell excitability in brain slices obtained from pre- (postnatal day [PD] 28-35) and post-pubertal (PD > 61) sham and NVHL animals. RESULTS: N-methyl d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA), and the D(1) agonist SKF38393 increased excitability of deep layer pyramidal neurons in a concentration-dependent manner. The opposite effect was observed with the D(2) agonist quinpirole. The effects of NMDA (but not AMPA) and SKF38393 on cell excitability were significantly higher in slices from NVHL animals, whereas quinpirole decrease of cell excitability was reduced. These differences were not observed in slices from pre-pubertal rats, suggesting that PFC DA and glutamatergic systems become altered after puberty in NVHL rats. CONCLUSIONS: A disruption of PFC dopamine-glutamate interactions might emerge after puberty in brains with an early postnatal deficit in hippocampal inputs, and this disruption could contribute to the manifestation of schizophrenia-like symptoms.
Assuntos
Dopamina/fisiologia , Ácido Glutâmico/fisiologia , Hipocampo/lesões , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Eletrofisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Hipocampo/fisiologia , N-Metilaspartato/farmacologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Gravidez , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaRESUMO
BACKGROUND: Among the diverse animal models proposed for schizophrenia, the neonatal ventral hippocampal lesion (NVHL) is one of the most widely used. However, its construct validity can be questioned because there is no evidence of a lesion present in schizophrenia. Other approaches that have tried to capture environmental influences on development include diverse models of maternal infection. METHODS: As the early postnatal days in rodents are equivalent to the third trimester of human pregnancy in terms of brain development, we decided to test whether a neonatal immune challenge with an injection of the bacterial endotoxin lipopolysaccharide (LPS) into the ventral hippocampus caused deficits in interneuron function similar to those reported for the NVHL. RESULTS: Neonatal LPS injection caused a persistent elevation in cytokines in several brain regions, deficits in prepulse inhibition of the acoustic startle response, and a loss of the periadolescent maturation in the response of prefrontal cortical fast-spiking interneurons to dopamine. CONCLUSIONS: The same phenotypes elicited by a NVHL can be obtained with an intrahippocampal immune challenge, suggesting that perinatal environmental factors can affect adult prefrontal interneuron maturation during adolescence.
Assuntos
Dopamina/farmacologia , Hipocampo/imunologia , Interneurônios/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Estimulação Acústica/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Agonistas de Dopamina/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/efeitos dos fármacos , Interneurônios/fisiologia , Lipopolissacarídeos/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/imunologiaAssuntos
Dopamina/fisiologia , Ácido Glutâmico/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Animais , Agonistas de Dopamina/farmacologia , Interações Medicamentosas , Eletrofisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
Adolescence is marked by profound psychological and neuroendocrine changes. Cognitive functions that depend on the prefrontal cortex and dopamine (DA), such as decision making, are acquired or refined during adolescence; yet, little is known about how neural circuits mature in the transition to adulthood. Here, we conducted electrophysiological recordings in rat brain slices, unveiling an enhancement of the excitability of interneurons, which are important for cortical network activity, by D(1) and D(2) DA receptors. The D(2) effect was observed in slices from adult (postnatal day [PD] > 50) but not preadolescent (PD < 36) animals suggesting a possible neural substrate for the maturation of DA-dependent prefrontal cortical functions during or after adolescence and identifying a critical neural population that could be involved in the periadolescent onset of neuropsychiatric disorders, such as schizophrenia.