RESUMO
Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others' lifespans outlast their "mindspans."
Assuntos
Região CA1 Hipocampal/patologia , Região CA3 Hipocampal/patologia , Envelhecimento Cognitivo , Células Piramidais/patologia , Sinapses/patologia , Animais , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344RESUMO
Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (Ih ) in the CA1 area increases with chronic mild stress. Reduction of Ih in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of Ih is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN channel expression. This approach led to a robust reduction in Ih in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN channel function in CA1 influences coping style.
Assuntos
Adaptação Psicológica/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Proteínas de Membrana/metabolismo , Peroxinas/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório , Hipocampo/citologia , Hipocampo/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/ultraestrutura , Masculino , Aprendizagem em Labirinto , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Peroxinas/genética , Células Piramidais/metabolismo , Natação/psicologiaRESUMO
Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.
Assuntos
Doença de Alzheimer/fisiopatologia , Região CA1 Hipocampal/fisiologia , Canalopatias/fisiopatologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Plasticidade Neuronal , Células Piramidais/fisiologia , Potenciais de Ação , Envelhecimento , Animais , Região CA1 Hipocampal/ultraestrutura , Modelos Animais de Doenças , Retículo Endoplasmático/fisiologia , Feminino , Masculino , Camundongos Transgênicos , Células Piramidais/ultraestruturaRESUMO
Aging-related impairments in hippocampus-dependent cognition have been attributed to maladaptive changes in the functional properties of pyramidal neurons within the hippocampal subregions. Much evidence has come from work on CA1 pyramidal neurons, with CA3 pyramidal neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing in the hippocampal circuit. Here, we use whole-cell current-clamp to demonstrate that aged rat (29-32 months) CA3 pyramidal neurons fire significantly more action potentials (APs) during theta-burst frequency stimulation and that this is associated with faster AP repolarization (i.e., narrower AP half-widths and enlarged fast afterhyperpolarization). Using a combination of patch-clamp physiology, pharmacology, Western blot analyses, immunohistochemistry, and array tomography, we demonstrate that these faster AP kinetics are mediated by enhanced function and expression of Kv4.2/Kv4.3 A-type K(+) channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K(+) channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state. Significance statement: Age-related learning deficits have been attributed, in part, to altered hippocampal pyramidal neuronal function with normal aging. Much evidence has come from work on CA1 neurons, with CA3 neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing. Hence, we conducted a series of experiments to identify the cellular mechanisms that underlie the hyperexcitability reported in the CA3 region. Contrary to CA1 neurons, we demonstrate that postburst afterhyperpolarization is not altered with aging and that aged CA3 pyramidal neurons are able to fire significantly more action potentials and that this is associated with faster action potential repolarization through enhanced expression of Kv4.2/Kv4.3 A-type K(+) channels, particularly within the cell bodies of CA3 pyramidal neurons.
Assuntos
Envelhecimento/fisiologia , Região CA3 Hipocampal/citologia , Potenciais da Membrana/fisiologia , Células Piramidais/fisiologia , Canais de Potássio Shal/metabolismo , Análise de Variância , Animais , Biofísica , Relação Dose-Resposta a Droga , Estimulação Elétrica , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/fisiologiaRESUMO
The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models. We also used patch-clamp physiology in these mice to probe for functional consequences of AD pathogenesis in ventral hippocampus, which we found bears significantly higher plaque burden in the aged ADTg group compared to corresponding dorsal regions. Despite dorsoventral differences in amyloid load, ventral CA1 pyramidal neurons of aged ADTg mice exhibited subthreshold physiological changes similar to those previously reported in dorsal neurons, indicative of an HCN channelopathy, but lacked exacerbated suprathreshold accommodation. Additionally, HCN channel function could be rescued by pharmacological manipulation of the endoplasmic reticulum. These observations suggest that an AD-linked HCN channelopathy emerges in both dorsal and ventral CA1 pyramidal neurons, but that the former encounter an additional integrative obstacle in the form of reduced intrinsic excitability.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Placa Amiloide/metabolismo , Células Piramidais/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Progressão da Doença , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Camundongos Transgênicos , Tamanho do Órgão , Técnicas de Patch-ClampRESUMO
Adult GnRH neurons exhibit a stereotypic morphology with a small soma, single axon, and single dendrite arising from the soma with little branching. The adult morphology of GnRH neurons in mice reflects an anatomical consolidation of dendrites over postnatal development. We examined this issue in rat GnRH neurons with biocytin filling in live hypothalamic slices from infant males, as adult littermates and in gonad-intact males, castrated males, and in males with one of three levels of testosterone (T) treatment. Somatic area and total dendritic length were significantly greater in infant males than in adults. Moreover, total numbers of dendrite branches were greater in infant males as compared with adults. The number of higher order branches and the lengths of higher order branches were also greater in infant males than in adults. Most interestingly, in adults a single dendrite arose from the somata, consistently at 180° from the axon. In contrast, prepubertal animals had an average of 2.2 ± 0.2 primary dendrites arising from somata (range, one to seven primary dendrites). Angles relative to the axon at which dendrites in prepubertal males emanated from GnRH somata were highly variable. Castration at 25 d of age and castration at 25 d of age with one of three levels of T treatment did not influence morphological parameters when GnRH neurons were examined between 40 d and 48 d of age. Thus, a spatially selective remodeling of primary dendrites and consolidation of distal GnRH dendritic arbors occurs during postnatal development and is largely independent of T.