RESUMO
The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.
Assuntos
Transtorno Autístico/fisiopatologia , Transtorno Autístico/terapia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/terapia , Animais , HumanosRESUMO
It is becoming evident that neurons express an unusual number of molecules that were originally thought to be specific to immune functions. One such molecule, class I major histocompatibility complex, is required in the activity-dependent refinement and plasticity of connections in the developing and adult central nervous system, demonstrating that molecules can perform critical roles in both systems. Recent studies reveal striking parallels between cellular signaling mechanisms in the immune and nervous systems that may provide unexpected insights into the development, function, and diseases of both systems.
Assuntos
Imunidade Celular/fisiologia , Plasticidade Neuronal/imunologia , Animais , Antígenos de Histocompatibilidade Classe I/fisiologia , Humanos , Neurônios/imunologia , Neurônios/fisiologia , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologiaRESUMO
Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).
Assuntos
Encéfalo/fisiologia , Complexo CD3/fisiologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Plasticidade Neuronal , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Encéfalo/crescimento & desenvolvimento , Complexo CD3/genética , Potenciais Pós-Sinápticos Excitadores , Perfilação da Expressão Gênica , Genes MHC Classe I , Corpos Geniculados/fisiologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/fisiologia , Antígenos de Histocompatibilidade Classe I/genética , Hibridização In Situ , Potenciação de Longa Duração , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Vias Neurais , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/crescimento & desenvolvimento , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Transdução de Sinais , Transmissão Sináptica , Vias VisuaisRESUMO
Neurotrophins have been proposed to participate in activity-dependent modifications of neuronal connectivity and synaptic efficacy. Preferential strengthening of active inputs requires restriction of putative neurotrophin-mediated synaptic potentiation to active synapses. Here we report that potentiation of synaptic efficacy by brain-derived neurotrophic factor (BDNF) is greatly facilitated by presynaptic depolarization at developing neuromuscular synapses. Brief depolarization in the presence of low-level BDNF results in a marked potentiation of both evoked and spontaneous synaptic transmission, whereas exposure to either BDNF or depolarization alone is without effect. This potentiation depends on the relative timing of depolarization and reflects an enhancement of transmitter secretion from the presynaptic neuron. Thus synapses made by active inputs may be selectively strengthened by secreted neurotrophins as part of activity-dependent refinement of developing connections or of mature synapses.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Potenciais de Ação , Animais , Cálcio/fisiologia , Células Cultivadas , Potenciais Evocados/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Técnicas de Patch-Clamp , Potássio/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Xenopus laevisRESUMO
Regional variations in the expression of a striatal enriched protein tyrosine phosphatase called STEP were studied in the adult rat brain by a combination of immunocytochemistry, lesion studies, Western blotting, and in situ hybridization. Monoclonal antibodies generated against STEP identified multiple polypeptides of M(r) 46, 37, 33 and a doublet of M(r) 64-66 kDa on Western blots. Although the three STEP immunoreactive bands with lower molecular weights were enriched in cytosolic fractions, the 64-66 kDa doublet was enriched in membrane fractions. All of the immunoreactive forms were abundant in the caudate-putamen and were present in lower amounts or were undetectable in other brain regions. In substantia nigra, the M(r) 64-66 kDa doublet was not detected but bands with M(r) 46, 37, and 33 kDa were present. Immunocytochemical and lesion experiments demonstrated that the cytosolic STEP isoforms present in the substantia nigra are in presynaptic axons originating from the projection neurons of the caudate putamen, which innervate this structure. Additional in situ hybridization studies showed that STEP mRNA expression patterns correlate with the patterns of immunocytochemical staining. These findings indicate that there are multiple polypeptide isoforms of STEP enriched in the basal ganglia and related structures which differ in terms of their intracellular locations and functional roles.