RESUMO
Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed â¼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Potenciais de Ação/fisiologia , Processamento Alternativo/genética , Processamento Alternativo/fisiologia , Animais , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Feminino , Células HEK293 , Homeostase/fisiologia , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Antígeno Neuro-Oncológico Ventral , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Proteínas de Ligação a RNA/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sinapses/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
Ca2+/calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other and have been inextricably intertwined ever since. However, like many marriages, it has had its up and downs. Based on the unique biochemical properties of CaMKII, it was proposed as a memory molecule before any physiological linkage was made to LTP. However, as reviewed here, the convincing linkage of CaMKII to synaptic physiology and behavior took many decades. New technologies were critical in this journey, including in vitro brain slices, mouse genetics, single-cell molecular genetics, pharmacological reagents, protein structure, and two-photon microscopy, as were new investigators attracted by the exciting challenge. This review tracks this journey and assesses the state of this marriage 40 years on. The collective literature impels us to propose a relatively simple model for synaptic memory involving the following steps that drive the process: 1) Ca2+ entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) CaMKII undergoes autophosphorylation resulting in constitutive, Ca2+-independent activity and exposure of a binding site for the NMDA receptor subunit GluN2B. 3) Active CaMKII translocates to the postsynaptic density (PSD) and binds to the cytoplasmic C-tail of GluN2B. 4) The CaMKII-GluN2B complex initiates a structural rearrangement of the PSD that may involve liquid-liquid phase separation. 5) This rearrangement involves the PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and their transmembrane AMPAR-regulatory protein (TARP) auxiliary subunits, resulting in an accumulation of AMPARs in the PSD that underlies synaptic potentiation. 6) The stability of the modified PSD is maintained by the stability of the CaMKII-GluN2B complex. 7) By a process of subunit exchange or interholoenzyme phosphorylation CaMKII maintains synaptic potentiation in the face of CaMKII protein turnover. There are many other important proteins that participate in enlargement of the synaptic spine or modulation of the steps that drive and maintain the potentiation. In this review we critically discuss the data underlying each of the steps. As will become clear, some of these steps are more firmly grounded than others, and we provide suggestions as to how the evidence supporting these steps can be strengthened or, based on the new data, be replaced. Although the journey has been a long one, the prospect of having a detailed cellular and molecular understanding of learning and memory is at hand.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Memória , Camundongos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Memória/fisiologia , Potenciação de Longa Duração/fisiologia , Aprendizagem , Hipocampo/fisiologiaRESUMO
Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII)1-3. However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP4-8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B9-14. Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Potenciação de Longa Duração , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/fisiologia , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Optogenética , Fosforilação , Ligação ProteicaRESUMO
Excitation-transcription coupling (E-TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E-TC makes a crucial contribution to learning and memory through its role in underpinning long-lasting synaptic enhancement in late-phase long-term potentiation and has more recently been linked to late-phase long-term depression: both processes require de novo gene transcription, mRNA translation and protein synthesis. E-TC begins with the activation of glutamate-gated N-methyl-D-aspartate-type receptors and voltage-gated L-type Ca2+ channels at the membrane and culminates in the activation of transcription factors in the nucleus. These receptors and ion channels mediate E-TC through mechanisms that include long-range signalling from the synapse to the nucleus and local interactions within dendritic spines, among other possibilities. Growing experimental evidence links these E-TC mechanisms to late-phase long-term potentiation and learning and memory. These advances in our understanding of the molecular mechanisms of E-TC mean that future efforts can focus on understanding its mesoscale functions and how it regulates neuronal network activity and behaviour in physiological and pathological conditions.
Assuntos
Plasticidade Neuronal , Receptores de N-Metil-D-Aspartato , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Plasticidade Neuronal/fisiologia , Potenciação de Longa Duração/fisiologia , Neurônios/metabolismo , Sinapses/metabolismo , Expressão Gênica , Hipocampo/fisiologiaRESUMO
Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc's canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc's synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Células de Purkinje/metabolismo , Sequência de Aminoácidos , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Animais , Sítios de Ligação , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Técnicas de Introdução de Genes , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Fosforilação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Células de Purkinje/citologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Sinapses/fisiologia , Transmissão SinápticaRESUMO
Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) plays a critical role in long-term potentiation (LTP), a well-established model for learning and memory through the enhancement of synaptic transmission. Biochemical studies indicate that CaMKII catalyzes a phosphotransferase (kinase) reaction of both itself (autophosphorylation) and of multiple downstream target proteins. However, whether either type of phosphorylation plays any role in the synaptic enhancing action of CaMKII remains hotly contested. We have designed a series of experiments to define the minimal requirements for the synaptic enhancement by CaMKII. We find that autophosphorylation of T286 and further binding of CaMKII to the GluN2B subunit are required both for initiating LTP and for its maintenance (synaptic memory). Once bound to the NMDA receptor, the synaptic action of CaMKII occurs in the absence of target protein phosphorylation. Thus, autophosphorylation and binding to the GluN2B subunit are the only two requirements for CaMKII in synaptic memory.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Potenciação de Longa Duração , Memória , Receptores de N-Metil-D-Aspartato , Sinapses , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Fosforilação , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Sinapses/metabolismo , Ratos , CamundongosRESUMO
Synaptic plasticity [long-term potentiation/depression (LTP/D)], is a cellular mechanism underlying learning. Two distinct types of early LTP/D (E-LTP/D), acting on very different time scales, have been observed experimentally-spike timing dependent plasticity (STDP), on time scales of tens of ms; and behavioral time scale synaptic plasticity (BTSP), on time scales of seconds. BTSP is a candidate for a mechanism underlying rapid learning of spatial location by place cells. Here, a computational model of the induction of E-LTP/D at a spine head of a synapse of a hippocampal pyramidal neuron is developed. The single-compartment model represents two interacting biochemical pathways for the activation (phosphorylation) of the kinase (CaMKII) with a phosphatase, with ion inflow through channels (NMDAR, CaV1,Na). The biochemical reactions are represented by a deterministic system of differential equations, with a detailed description of the activation of CaMKII that includes the opening of the compact state of CaMKII. This single model captures realistic responses (temporal profiles with the differing timescales) of STDP and BTSP and their asymmetries. The simulations distinguish several mechanisms underlying STDP vs. BTSP, including i) the flow of [Formula: see text] through NMDAR vs. CaV1 channels, and ii) the origin of several time scales in the activation of CaMKII. The model also realizes a priming mechanism for E-LTP that is induced by [Formula: see text] flow through CaV1.3 channels. Once in the spine head, this small additional [Formula: see text] opens the compact state of CaMKII, placing CaMKII ready for subsequent induction of LTP.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Plasticidade Neuronal , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Plasticidade Neuronal/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismoRESUMO
Transforming growth factor ß (TGFß) is required for long-term memory (LTM) for sensitization in Aplysia. When LTM is induced using a two-trial training protocol, TGFß inhibition only blocks LTM when administrated at the second, not the first trial. Here, we show that TGFß acts as a "repetition detector" during the induction of two-trial LTM. Secretion of the biologically inert TGFß proligand must coincide with its proteolytic activation by the Bone morphogenetic protein-1 (BMP-1/Tolloid) metalloprotease, which occurs specifically during trial two of our two-trial training paradigm. This paradigm establishes long-term synaptic facilitation (LTF), the cellular correlate of LTM. BMP-1 application paired with a single serotonin (5HT) pulse induced LTF, whereas neither a single 5HT pulse nor BMP-1 alone effectively did so. On the other hand, inhibition of endogenous BMP-1 activity blocked the induction of two-trial LTF. These results suggest a unique role for TGFß in the interaction of repeated trials: during learning, repeated stimuli engage separate steps of the TGFß cascade that together are necessary for the induction of long-lasting memories.
Assuntos
Potenciação de Longa Duração , Fator de Crescimento Transformador beta , Animais , Potenciação de Longa Duração/fisiologia , Fator de Crescimento Transformador beta/farmacologia , Plasticidade Neuronal/fisiologia , Memória de Longo Prazo/fisiologia , Aplysia/fisiologiaRESUMO
Memory formation is typically divided into phases associated with encoding, storage, consolidation, and retrieval. The neural determinants of these phases are thought to differ. This study first investigated the impact of the experience of novelty in rats incurred at a different time, before or after, the precise moment of memory encoding. Memory retention was enhanced. Optogenetic activation of the locus coeruleus mimicked this enhancement induced by novelty, both when given before and after the moment of encoding. Optogenetic activation of the locus coeruleus also induced a slow-onset potentiation of field potentials in area CA1 of the hippocampus evoked by CA3 stimulation. Despite the locus coeruleus being considered a primarily noradrenergic area, both effects of such stimulation were blocked by the dopamine D1/D5 receptor antagonist SCH 23390. These findings substantiate and enrich the evidence implicating the locus coeruleus in cellular aspects of memory consolidation in hippocampus.
Assuntos
Locus Cerúleo , Optogenética , Ratos , Animais , Locus Cerúleo/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Norepinefrina/farmacologia , Potenciação de Longa Duração/fisiologiaRESUMO
Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2α (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2α phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2α in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories.
Assuntos
Astrócitos , Potenciação de Longa Duração , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/genética , Hipocampo/fisiologia , Biossíntese de Proteínas , Região CA1 Hipocampal , Memória de Longo Prazo/fisiologiaRESUMO
Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.
Assuntos
Potenciação de Longa Duração , Neocórtex , Ratos , Animais , Potenciação de Longa Duração/fisiologia , Neurônios , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Plasticidade Neuronal/fisiologia , Hipocampo/fisiologiaRESUMO
Somatostatin-expressing interneurons (SOMIs) in the mouse dentate gyrus (DG) receive feedforward excitation from granule cell (GC) mossy fiber (MF) synapses and provide feedback lateral inhibition onto GC dendrites to support environment representation in the DG network. Although this microcircuitry has been implicated in memory formation, little is known about activity-dependent plastic changes at MF-SOMI synapses and their influence on behavior. Here, we report that the metabotropic glutamate receptor 1α (mGluR1α) is required for the induction of associative long-term potentiation (LTP) at MF-SOMI synapses. Pharmacological block of mGluR1α, but not mGluR5, prevented synaptic weight changes. LTP at MF-SOMI synapses was postsynaptically induced, required increased intracellular Ca2+, involved G-protein-mediated and Ca2+-dependent (extracellular signal-regulated kinase) ERK1/2 pathways, and the activation of NMDA receptors. Specific knockdown of mGluR1α in DG-SOMIs by small hairpin RNA expression prevented MF-SOMI LTP, reduced SOMI recruitment, and impaired object location memory. Thus, postsynaptic mGluR1α-mediated MF-plasticity at SOMI input synapses critically supports DG-dependent mnemonic functions.
Assuntos
Fibras Musgosas Hipocampais , Plasticidade Neuronal , Camundongos , Animais , Fibras Musgosas Hipocampais/fisiologia , Plasticidade Neuronal/fisiologia , Interneurônios/fisiologia , Potenciação de Longa Duração/fisiologia , Sinapses/metabolismo , Somatostatina/metabolismo , Giro Denteado/metabolismo , Transmissão SinápticaRESUMO
Adult-born granule cells (abGCs) exhibit a transient period of elevated synaptic plasticity that plays an important role in hippocampal function. Various mechanisms have been implicated in this critical period for enhanced plasticity, including minimal GABAergic inhibition and high intrinsic excitability conferred by T-type Ca2+ channels. Here we assess the contribution of synaptic inhibition and intrinsic excitability to long-term potentiation (LTP) in abGCs of adult male and female mice using perforated patch recordings. We show that the timing of critical period plasticity is unaffected by intact GABAergic inhibition such that 4-6-week-old abGCs exhibit LTP that is absent by 8â weeks. Blocking GABAA receptors, or partial blockade of GABA release from PV and nNos-expressing interneurons by a µ-opioid receptor agonist, strongly enhances LTP in 4-week-old GCs, suggesting that minimal inhibition does not underlie critical period plasticity. Instead, the closure of the critical period coincides with a reduction in the contribution of T-type Ca2+ channels to intrinsic excitability, and a selective T-type Ca2+ channel antagonist prevents LTP in 4-week-old but not mature GCs. Interestingly, whole-cell recordings that facilitate T-type Ca2+ channel activity in mature GCs unmasks LTP (with inhibition intact) that is also sensitive to a T-type Ca2+ channel antagonist, suggesting T-type channel activity in mature GCs is suppressed by native intracellular signaling. Together these results show that abGCs use T-type Ca2+ channels to overcome inhibition, providing new insight into how high intrinsic excitability provides young abGCs a competitive advantage for experience-dependent synaptic plasticity.
Assuntos
Potenciação de Longa Duração , Neurônios , Camundongos , Animais , Masculino , Feminino , Neurônios/fisiologia , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Hipocampo/fisiologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
The outgrowth and stabilization of nascent dendritic spines are crucial processes underlying learning and memory. Most new spines retract shortly after growth; only a small subset is stabilized and integrated into the new circuit connections that support learning. New spine stabilization has been shown to rely upon activity-dependent molecular mechanisms that also contribute to long-term potentiation (LTP) of synaptic strength. Indeed, disruption of the activity-dependent targeting of the kinase CaMKIIα to the GluN2B subunit of the NMDA-type glutamate receptor disrupts both LTP and activity-dependent stabilization of new spines. Yet it is not known which of CaMKIIα's many enzymatic and structural functions are important for new spine stabilization. Here, we used two-photon imaging and photolysis of caged glutamate to monitor the activity-dependent stabilization of new dendritic spines on hippocampal CA1 neurons from mice of both sexes in conditions where CaMKIIα functional and structural interactions were altered. Surprisingly, we found that inhibiting CaMKIIα kinase activity either genetically or pharmacologically did not impair activity-dependent new spine stabilization. In contrast, shRNA knockdown of CaMKIIα abolished activity-dependent new spine stabilization, which was rescued by co-expressing shRNA-resistant full-length CaMKIIα, but not by a truncated monomeric CaMKIIα. Notably, overexpression of phospho-mimetic CaMKIIα-T286D, which exhibits activity-independent targeting to GluN2B, enhanced basal new spine survivorship in the absence of additional glutamatergic stimulation, even when kinase activity was disrupted. Together, our results support a model in which nascent dendritic spine stabilization requires structural and scaffolding interactions mediated by dodecameric CaMKIIα that are independent of its enzymatic activities.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Espinhas Dendríticas , Feminino , Masculino , Camundongos , Animais , Espinhas Dendríticas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Potenciação de Longa Duração/fisiologia , Hipocampo/fisiologia , RNA Interferente PequenoRESUMO
Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of HippâNAc synapses is rewarding, and mice can establish learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigated sex differences in the mechanisms underlying HippâNAc LTP using whole-cell electrophysiology and pharmacology. We observed similarities in basal synaptic strength between males and females and found that LTP occurs postsynaptically with similar magnitudes in both sexes. However, key sex differences emerged as LTP in males required NMDA receptors (NMDAR), whereas LTP in females utilized an NMDAR-independent mechanism involving L-type voltage-gated Ca2+ channels (VGCCs) and estrogen receptor α (ERα). We also uncovered sex-similar features as LTP in both sexes depended on CaMKII activity and occurred independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.
Assuntos
Hipocampo , Potenciação de Longa Duração , Camundongos Endogâmicos C57BL , Núcleo Accumbens , Receptores de N-Metil-D-Aspartato , Caracteres Sexuais , Sinapses , Animais , Masculino , Núcleo Accumbens/fisiologia , Potenciação de Longa Duração/fisiologia , Feminino , Camundongos , Sinapses/fisiologia , Hipocampo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Neurônios/fisiologia , Neurônios Espinhosos MédiosRESUMO
The impact of dopamine on synaptic plasticity and cognitive function following seizure is not well understood. Here, using optogenetics in the freely behaving animal, we examined exploratory behavior and short-term memory in control and kindled male mice during tonic stimulation of dopaminergic neurons within the ventral tegmental area (VTA). Furthermore, using field potential recording, we compared the effect of dopamine on synaptic plasticity in stratum radiatum and stratum oriens layers of both ventral and dorsal hippocampal CA1 regions, and again in both control and kindled male mice. Our results demonstrate that tonic stimulation of VTA dopaminergic neurons enhances novelty-driven exploration and short-term spatial memory in kindled mice, essentially rescuing the seizure-induced cognitive impairment. In addition, we found that dopamine has a dual effect on LTP in control versus kindled mice, such that application of dopamine prevented LTP induction in slices from control mice, but rescued LTP in slices taken from the kindled animal. Taken together, our results highlight the potential for dopaminergic modulation in improving synaptic plasticity and cognitive function following seizure.
Assuntos
Dopamina , Hipocampo , Camundongos , Masculino , Animais , Dopamina/farmacologia , Hipocampo/fisiologia , Região CA1 Hipocampal/fisiologia , Convulsões , Cognição , Potenciação de Longa Duração/fisiologiaRESUMO
There has been considerable controversy about pre- versus postsynaptic expression of memory-related long-term potentiation (LTP), with corresponding disputes about underlying mechanisms. We report here an instance in male mice, in which both types of potentiation are expressed but in separate branches of the same hippocampal afferent. Induction of LTP in the dentate gyrus (DG) branch of the lateral perforant path (LPP) reduces paired-pulse facilitation, is blocked by antagonism of cannabinoid receptor type 1, and is not affected by suppression of postsynaptic actin polymerization. These observations are consistent with presynaptic expression. The opposite pattern of results was obtained in the LPP branch that innervates the distal dendrites of CA3: LTP did not reduce paired-pulse facilitation, was unaffected by the cannabinoid receptor blocker, and required postsynaptic actin filament assembly. Differences in the two LPP termination sites were also noted for frequency facilitation of synaptic responses, an effect that was reproduced in a two-step simulation by small adjustments to vesicle release dynamics. These results indicate that different types of glutamatergic neurons impose different forms of filtering and synaptic plasticity on their afferents. They also suggest that inputs are routed to, and encoded by, different sites within the hippocampus depending upon the pattern of activity arriving over the parent axon.
Assuntos
Giro Denteado , Potenciação de Longa Duração , Masculino , Camundongos , Animais , Potenciação de Longa Duração/fisiologia , Giro Denteado/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Estimulação Elétrica/métodosRESUMO
The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.
Assuntos
Hipocampo , Deficiência Intelectual , Histona Desmetilases com o Domínio Jumonji , Consolidação da Memória , Memória de Longo Prazo , Animais , Hipocampo/metabolismo , Camundongos , Masculino , Feminino , Deficiência Intelectual/genética , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Camundongos Endogâmicos C57BL , Proteínas de Ligação a DNARESUMO
Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell-type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons, or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain.
Assuntos
Astrócitos , Potenciação de Longa Duração , Receptores de Dopamina D1 , Receptores de Dopamina D5 , Sinapses , Animais , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/genética , Potenciação de Longa Duração/fisiologia , Astrócitos/metabolismo , Astrócitos/fisiologia , Camundongos , Masculino , Receptores de Dopamina D5/metabolismo , Receptores de Dopamina D5/agonistas , Receptores de Dopamina D5/genética , Feminino , Sinapses/fisiologia , Sinapses/metabolismo , Gânglios Espinais/citologia , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/citologia , Camundongos Transgênicos , Camundongos Endogâmicos C57BLRESUMO
The mechanisms utilized by neurons to regulate the efficacy of phasic and tonic inhibition and their impacts on synaptic plasticity and behavior are incompletely understood. Cleft lip and palate transmembrane protein 1 (Clptm1) is a membrane-spanning protein that interacts with multiple γ-aminobutyric acid type A receptor (GABAAR) subunits, trapping them in the endoplasmic reticulum and Golgi network. Overexpression and knock-down studies suggest that Clptm1 modulates GABAAR-mediated phasic inhibition and tonic inhibition as well as activity-induced inhibitory synaptic homeostasis in cultured hippocampal neurons. To investigate the role of Clptm1 in the modulation of GABAARs in vivo, we generated Clptm1 knock-out (KO) mice. Here, we show that genetic KO of Clptm1 elevated phasic and tonic inhibitory transmission in both male and female heterozygous mice. Although basal excitatory synaptic transmission was not affected, Clptm1 haploinsufficiency significantly blocked high-frequency stimulation-induced long-term potentiation (LTP) in hippocampal CA3âCA1 synapses. In the hippocampus-dependent contextual fear-conditioning behavior task, both male and female Clptm1 heterozygous KO mice exhibited impairment in contextual fear memory. In addition, LTP and contextual fear memory were rescued by application of L-655,708, a negative allosteric modulator of the extrasynaptic GABAAR α5 subunit. These results suggest that haploinsufficiency of Clptm1 contributes to cognitive deficits through altered synaptic transmission and plasticity by elevation of inhibitory neurotransmission, with tonic inhibition playing a major role.