Individual NMDA receptor GluN2 subunit signaling domains differentially regulate the postnatal maturation of hippocampal excitatory synaptic transmission and plasticity but not dendritic morphology.

N-methyl-d-aspartate receptors (NMDARs) at hippocampal excitatory synapses undergo a late postnatal shift in subunit composition, from an initial prevalence of GluN2B subunit incorporation to a later predominance of GluN2A. This GluN2B to GluN2A shift alters NMDAR calcium conductance dynamics and intracellular molecular signaling that are individually regulated by distinct GluN2 signaling domains and temporally align with developmental alterations in dendritic and synaptic plasticity. However, the impacts of individual GluN2B to GluN2A signaling domains on neuronal development remain unknown. Ionotropic and intracellular signaling domains of GluN2 subunits were separated by creating chimeric GluN2 subunits that were expressed in two transgenic mouse lines. Western blot and immunoprecipitation revealed that roughly one third of native synaptic NMDARs were replaced by transformed NMDARs without altering total synaptic NMDAR content. Schaffer collateral synaptic strength was transiently increased in acutely prepared hippocampal slices at just over 3 weeks of age in animals overexpressing the GluN2B carboxy terminus. Long-term potentiation (LTP) induction following lower frequency stimulation was regulated by GluN2 ionotropic signaling domains in an age-dependent manner and LTP maintenance was enhanced by overexpression of the GluN2B CTD in mature animals. After higher frequency stimulation, the induction and maintenance of LTP were increased in young adult animals overexpressing the GluN2B ionotropic signaling domains but reduced in juveniles just over 3 weeks of age. Confocal imaging of green fluorescent protein (GFP)- labeled CA1 pyramidal neurons revealed no alterations in dendritic morphology or spine density in mice expressing chimeric GluN2 subunits. These results illustrate how individual GluN2 subunit signaling domains do or do not control physiological and morphological development of hippocampal excitatory neurons and better clarify the neurobiological factors that govern hippocampal maturation. SIGNIFICANCE STATEMENT: A developmental reduction in the magnitude of hippocampal long-term synaptic potentiation (LTP) and a concomitant improvement in spatial maze performance coincide with greater incorporation of GluN2A subunits into synaptic NMDARs. Corroborating our prior discovery that overexpression of GluN2A-type ionotropic signaling domains enables context-based navigation in immature mice, GluN2A-type ionotropic signaling domain overexpression reduces LTP induction threshold and magnitude in immature mice. Also, we previously found that GluN2B carboxy terminal domain (CTD) overexpression enhances long-term spatial memory in mature mice and now report that the GluN2B CTD is associated with greater amplitude of LTP after induction in mature mice. Thus, the late postnatal maturation of context encoding likely relies on a shift toward GluN2A-type ionotropic signaling and a reduction in the threshold to induce LTP while memory consolidation and LTP maintenance are regulated by GluN2B subunit CTD signaling.

Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors differentially alters spatial learning and memory in juvenile rats younger and older than three weeks.

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

Behind the scenes: Are latent memories supported by calcium independent plasticity?

N-methyl-D-aspartate receptors (NMDARs) can be considered to be the de facto "plasticity" receptors in the brain due to their central role in the activity-dependent modification of neuronal morphology and synaptic transmission. Since the 1980s, research on NMDARs has focused on the second messenger properties of calcium and the downstream signaling pathways that mediate alterations in neural form and function. Recently, NMDARs were shown to drive activity-dependent synaptic plasticity without calcium influx. How this "nonionotropic" plasticity occurs in vitro is becoming clearer, but research on its involvement in behavior and cognition is in its infancy. There is a partial overlap in the downstream signaling molecules that are involved in ionotropic and nonionotropic NMDAR-dependent plasticity. Given this, and prior studies of the cognitive impacts of ionotropic NMDAR plasticity, a preliminary model explaining how NMDAR nonionotropic plasticity affects learning and memory can be established. We hypothesize that nonionotropic NMDAR plasticity takes part in latent memory encoding in immature rodents through nonassociative depression of synaptic efficacy, and possibly shrinking of dendritic spines. Further, the late postnatal alteration in NMDAR composition in the hippocampus appears to reduce nonionotropic signaling and remove a restriction on memory retrieval. This framework substantially alters the canonical model of NMDAR involvement in spatial cognition and hippocampal maturation and provides novel and exciting inroads for future studies.

Hippocampal gamma rhythms during Y-maze navigation in the juvenile rat.

The neurobiology of postnatal hippocampal development in rodents is receiving increased attention as a means to address neurodevelopmental questions and to better understand the neural code(s) for spatial navigation in adulthood. We previously showed that spontaneous alternation (SA) in a Y-maze, which emerges at the end of the third postnatal week, was related to changes in fast glutamatergic synaptic transmission. In adults, oscillations in the hippocampal local field potential (LFP) (i.e., theta, 4-12 Hz; slow gamma, 25-55 Hz; and fast gamma, 65-100 Hz) have been shown to coordinate the activity of spatially tuned cell types in the hippocampus during route planning and execution. Other investigators have shown that theta activity matures during the first month of life. However, relationships between developmental alterations in gamma oscillations and cognitive function have not been investigated in juveniles, and the impact of developmental changes in excitatory synaptic transmission on network activity remains unclear. We implanted rats at postnatal day 14 to record LFPs from the synaptic layer of area CA1 during Y-maze exploration at postnatal Days 18, 19, 23, and 24. The positive allosteric modulator of AMPA receptors, CX614, or vehicle was administered prior to each test. We found that slow gamma peak frequency, but not peak power, remained constant across this age range. Fast gamma event rate increased with increasing age, while peak frequency decreased. AMPA receptor modulation impacted slow and fast gamma differently at different ages. Furthermore, gamma events showed relationships with novelty and movement speed that differed based on gamma sub-band (slow vs. fast). These results support the presence of environmentally-driven gamma oscillations in hippocampal network activity prior to the end of the third postnatal week of development. Differential refinement of slow and fast gamma occurring across the subsequent week supports involvement in the emergence of spatial navigation ability.

A Barnes maze for juvenile rats delineates the emergence of spatial navigation ability.

The neural bases of cognition may be greatly informed by relating temporally defined developmental changes in behavior with concurrent alterations in neural function. A robust improvement in performance in spatial learning and memory tasks occurs at 3 wk of age in rodents. We reported that the developmental increase of spontaneous alternation in a Y-maze was related to changes in temporal dynamics of fast glutamatergic synaptic transmission in the hippocampus. We also showed that, during allothetic behaviors in the Y-maze, network oscillation power increased at frequency bands known to support spatial learning and memory in adults. However, there are no discrete learning and memory phases during free exploration in the Y-maze. Thus, we adapted the Barnes maze for use with juvenile rats. Following a single platform exposure in dim light on the day before training (to encourage exploration), animals were trained on the subsequent 2 d in bright light to find a hidden escape box and then underwent a memory test 24 h later. During escape training, the older animals learned the task in 1 d, while the younger animals required 2 d and did not reach the performance of older animals. Long-term memory performance was also superior in the older animals. Thus, we have validated the use of the Barnes maze for this developmental period and established a timeline for the ontogeny of spatial navigation ability in this maze around 3 wk of age. Subsequent work will pair in vivo recording of hippocampal oscillations and single units with this task to help identify how hippocampal maturation might relate to performance improvements.

Separate functional properties of NMDARs regulate distinct aspects of spatial cognition.

N-methyl-d-aspartate receptors (NMDARs) at excitatory synapses are central to activity-dependent synaptic plasticity and learning and memory. NMDARs act as ionotropic and metabotropic receptors by elevating postsynaptic calcium concentrations and by direct intracellular protein signaling. In the forebrain, these properties are controlled largely by the auxiliary GluN2 subunits, GluN2A and GluN2B. While calcium conductance through NMDAR channels and intracellular protein signaling make separate contributions to synaptic plasticity, it is not known if these properties individually influence learning and memory. To address this issue, we created chimeric GluN2 subunits containing the amino-terminal domain and transmembrane domains from GluN2A or GluN2B fused to the carboxy-terminal domain of GluN2B (termed ABc) or GluN2A ATD (termed BAc), respectively, and expressed these mutated GluN2 subunits in transgenic mice. Expression was confirmed at the mRNA level and protein subunit translation and translocation into dendrites were observed in forebrain neurons. In the spatial version of the Morris water maze, BAc mice displayed signs of a learning deficit. In contrast, ABc animals performed similarly to wild-types during training, but showed a more direct approach to the goal location during a long-term memory test. There was no effect of ABc or BAc expression in a nonspatial water escape task. Since background expression is predominantly GluN2A in mature animals, the results suggest that spatial learning is more sensitive to manipulations of the amino-terminal domain and transmembrane domains (calcium conductance) and long-term memory is regulated more by the carboxy-terminal domain (intracellular protein signaling).

Multimodal Plasticity in Dorsal Striatum While Learning a Lateralized Navigation Task.

Growing evidence supports a critical role for the dorsal striatum in cognitive as well as motor control. Both lesions and in vivo recordings demonstrate a transition in the engaged dorsal striatal subregion, from dorsomedial to dorsolateral, as skill performance shifts from an attentive phase to a more automatic or habitual phase. What are the neural mechanisms supporting the cognitive and behavioral transitions in skill learning? To pursue this question, we used T-maze training during which rats transition from early, attentive (dorsomedial) to late habitual (dorsolateral) performance. Following early or late training, we performed the first direct comparison of bidirectional synaptic plasticity in striatal brain slices, and the first evaluation of striatal synaptic plasticity by hemisphere relative to a learned turn. Consequently, we find that long-term potentiation and long-term depression are independently modulated with learning rather than reciprocally linked as previously suggested. Our results establish that modulation of evoked synaptic plasticity with learning depends on striatal subregion, training stage, and hemisphere relative to the learned turn direction. Exclusive to the contralateral hemisphere, intrinsic excitability is enhanced in dorsomedial relative to dorsolateral medium spiny neurons early in training and population responses are dampened late in training. Neuronal reconstructions indicate dendritic remodeling after training, which may represent a novel form of pruning. In conclusion, we describe region- and hemisphere-specific changes in striatal synaptic, intrinsic, and morphological plasticity which correspond to T-maze learning stages, and which may play a role in the cognitive transition between attentive and habitual strategies. Significance statement: We investigated neural plasticity in dorsal striatum from rats that were briefly or extensively trained on a directional T-maze task. Our results demonstrate that both the extent of training and the direction a rat learns to turn control the location and type of change in synaptic plasticity. In addition, brief training produces changes in neuron excitability only within one striatal subregion, whereas all training produces widespread changes in dendritic morphology. Our results suggest that activity in dorsomedial striatum strengthens the rewarded turn after brief training, whereas activity in dorsolateral striatum suppresses unrewarded turns after extensive training. This study illuminates how plasticity mediates learning using a task recognized for transitioning subjects from attentive to automatic performance.

Differential Arc expression in the hippocampus and striatum during the transition from attentive to automatic navigation on a plus maze.

The strategies utilized to effectively perform a given task change with practice and experience. During a spatial navigation task, with relatively little training, performance is typically attentive enabling an individual to locate the position of a goal by relying on spatial landmarks. These (place) strategies require an intact hippocampus. With task repetition, performance becomes automatic; the same goal is reached using a fixed response or sequence of actions. These (response) strategies require an intact striatum. The current work aims to understand the activation patterns across these neural structures during this experience-dependent strategy transition. This was accomplished by region-specific measurement of activity-dependent immediate early gene expression among rats trained to different degrees on a dual-solution task (i.e., a task that can be solved using either place or response navigation). As expected, rats increased their reliance on response navigation with extended task experience. In addition, dorsal hippocampal expression of the immediate early gene Arc was considerably reduced in rats that used a response strategy late in training (as compared with hippocampal expression in rats that used a place strategy early in training). In line with these data, vicarious trial and error, a behavior linked to hippocampal function, also decreased with task repetition. Although Arc mRNA expression in dorsal medial or lateral striatum alone did not correlate with training stage, the ratio of expression in the medial striatum to that in the lateral striatum was relatively high among rats that used a place strategy early in training as compared with the ratio among over-trained response rats. Altogether, these results identify specific changes in the activation of dissociated neural systems that may underlie the experience-dependent emergence of response-based automatic navigation.

Developmental changes in structural and functional properties of hippocampal AMPARs parallels the emergence of deliberative spatial navigation in juvenile rats.

The neural mechanisms that support the late postnatal development of spatial navigation are currently unknown. We investigated this in rats and found that an increase in the duration of AMPAR-mediated synaptic responses in the hippocampus was related to the emergence of spatial navigation. More specifically, spontaneous alternation rate, a behavioral indicator of hippocampal integrity, increased at the end of the third postnatal week in association with increases in AMPAR response duration at SC-CA1 synapses and synaptically driven postsynaptic discharge of CA1 pyramidal neurons. Pharmacological prolongation of glutamatergic synaptic transmission in juveniles increased the spontaneous alternation rate and CA1 postsynaptic discharge and reduced the threshold for the induction of activity-dependent synaptic plasticity at SC-CA1 synapses. A decrease in GluA1 and increases in GluA3 subunit and transmembrane AMPAR regulatory protein (TARP) expression at the end of the third postnatal week provide a molecular explanation for the increase in AMPAR response duration and reduced efficacy of AMPAR modulators with increasing age. A shift in the composition of AMPARs and increased association with AMPAR protein complex accessory proteins at the end of the third postnatal week likely "turns on" the hippocampus by increasing AMPAR response duration and postsynaptic excitability and reducing the threshold for activity-dependent synaptic potentiation.

A secondary working memory challenge preserves primary place strategies despite overtraining.

Learning by repetition engages distinct cognitive strategies whose contributions are adjusted with experience. Early in learning, performance relies upon flexible, attentive strategies. With extended practice, inflexible, automatic strategies emerge. This transition is thought fundamental to habit formation and applies to human and animal cognition. In the context of spatial navigation, place strategies are flexible, typically employed early in training, and rely on the spatial arrangement of landmarks to locate a goal. Response strategies are inflexible, become dominant after overtraining, and utilize fixed motor sequences. Although these strategies can operate independently, they have also been shown to interact. However, since previous work has focused on single-choice learning, if and how these strategies interact across sequential choices remains unclear. To test strategy interactions across sequential choices, we utilized various two-choice spatial navigation tasks administered on the Opposing Ts maze, an apparatus for rodents that permits experimental control over strategy recruitment. We found that when a second choice required spatial working memory, the transition to response navigation on the first choice was blocked. Control experiments specified this effect to the cognitive aspects of the secondary task. In addition, response navigation, once established on a single choice, was not reversed by subsequent introduction of a secondary choice reliant on spatial working memory. These results demonstrate that performance strategies interact across choices, highlighting the sensitivity of strategy use to the cognitive demands of subsequent actions, an influence from which overtrained rigid actions may be protected.

Postnatal alterations in induction threshold and expression magnitude of long-term potentiation and long-term depression at hippocampal synapses.

Activity-dependent synaptic plasticity refines neural networks during development and subserves information processing in adulthood. Previous research has revealed postnatal alterations in synaptic plasticity at nearly all forebrain synapses, suggesting different forms of synaptic plasticity may contribute to network development and information processing. To assess possible relationships between modifications in synaptic plasticity and maturation of cognitive ability, we examined excitatory synaptic function in area CA1 of the mouse hippocampus ∼3 weeks of age, when hippocampal-dependent learning and memory abilities first emerge. Long-term potentiation (LTP) and depression (LTD) of synaptic efficacy were observed in slices from juvenile animals younger than 3 weeks of age. Both pre- and postsynaptic mechanisms supported LTP and LTD in juveniles. After the third postnatal week, the magnitude of LTP was reduced and the threshold for postsynaptic induction was reduced, but the threshold for presynaptic induction was increased. The reduced threshold for postsynaptic LTP appeared to be due, partly, to an increase in baseline excitatory synaptic strength, which likely permitted greater postsynaptic depolarization during induction. Low frequency stimulation did not induce LTD at this more mature stage, but it blocked subsequent induction of LTP, suggesting metaplastic differences across age groups. Late postnatal modifications in activity-dependent synaptic plasticity might reflect attenuation of mechanisms more closely tied to network formation (presynaptic potentiation and pre- and postsynaptic depression) and unmasking of mechanisms underlying information processing and storage (associative postsynaptic potentiation), which likely impact the integrative capacity of the network and regulate the emergence of adult-like cognitive abilities.

Adult Health and Early Life Adversity: Behind the Curtains of Maternal Care Research.

The quality of one's adult health and the chances of maintaining cognitive ability in aging stem directly from the quality of care one receives as an infant. Formal studies of maternal care can be traced back at least a century. Revelations of behavioral outcomes after maternal deprivation in primates were followed by discoveries of systemic and brain growth factors mediated by the caregiver-offspring relationship in rodents. More recently, much of the genetic/epigenetic bases of maternal care has been defined and positively linked to adult health and cognitive ability in senescence. The history of this field is both tragic and fascinating. The early primate work, while informative, was abusive. The initial rodent work was ridiculed before its importance was recognized. The final lesson learned is that infant/toddler care matters a lot. Today, we have a better understanding of the biology underlying maternal care and its transmission across generations as well as a scientific basis for massaging premature infants and hugging our children.

Anti-glucocorticoid gene therapy reverses the impairing effects of elevated corticosterone on spatial memory, hippocampal neuronal excitability, and synaptic plasticity.

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading enzyme in hippocampal neurons would attenuate the negative impact of an excessive elevation in GC levels on synaptic physiology and spatial memory. We tested this by expressing 11-beta-hydroxysteroid dehydrogenase (type II) in dentate gyrus granule cells during a 3 d GC treatment followed by examination of synaptic responses in hippocampal slices or spatial performance in the Morris water maze. In adrenalectomized rats with basal GC replacement, additional GC treatments for 3 d reduced synaptic strength and promoted the expression of long-term depression at medial perforant path synapses, increased granule cell and CA1 pyramidal cell excitability, and impaired spatial reference memory (without influencing learning). Expression of 11-beta-hydroxysteroid dehydrogenase (type II), mostly in mature dentate gyrus granule cells, reversed the effects of high GC levels on granule cell and pyramidal cell excitability, perforant path synaptic plasticity, and spatial memory. These data demonstrate the ability of neuroprotective gene expression limited to a specific cell population to both locally and trans-synaptically offset neurophysiological disruptions produced by prolonged increases in circulating stress hormones. This report supplies the first physiological explanation for previously demonstrated cognitive sparing by anti-stress gene therapy approaches and lends additional insight into the hippocampal processes that are important for memory.

Spatial Learning Is Impaired in Male Pubertal Rats Following Neonatal Daily but Not Randomly Spaced Maternal Deprivation.

Severe early life stress has long been associated with neuropsychological disorders in adulthood, including depression, schizophrenia, post-traumatic stress disorder, and memory dysfunction. To some extent, all of these conditions involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced negative feedback inhibition of cortisol release in adulthood. However, the time course for mental health and hormonal outcomes across life stages and the attributes of early life stress that direct the behavioral and biological alterations is not fully understood. We designed our studies to compare outcomes of the two most common maternal deprivation schedules on cognitive ability prior to adulthood. We exposed rat pups to daily or randomly spaced maternal separation bouts within the first 3 weeks of life and examined cognitive performance, neurotrophic signaling, and stress and immune system markers during puberty. We found that the daily separation schedule impaired spatial learning while the randomly spaced schedule did not alter maze performance relative to normally reared control animals. Animals that underwent daily separation showed a tendency for reduced body weight compared to the randomly spaced condition, but there were no differences in adrenal weight. Thymus weight normalized by body weight was increased following daily separation compared to random separation and control conditions. Plasma corticosterone levels measured after behavior testing did not differ amongst experimental groups and there was no impact of TrKB receptor inhibition. Combined, the results show that different early life stress schedules produce different behavioral and biological outcomes when measured at puberty. Combined with prior findings from more mature animals, the results presented here suggest that daily neonatal stress produces varied alterations in spatial cognition at different life stages with a transient learning deficit at puberty preceding a more persistent and a progressive memory impairment through adulthood and into aging.

Aversive conditioning in the tardigrade, Dactylobiotus dispar.

Defensive responses to threatening events in the environment are displayed by a vast number of animals, both vertebrate and invertebrate. These defensive responses can be associated with salient neutral stimuli that are present along with the threatening stimulus. This is referred to as aversive conditioning. Animals with more simple nervous systems, such as Aplysia, C elegans, and Drosophila, have facilitated identification of some the physiological processes that support aversive conditioning. Perhaps even more basic information regarding the neurobiology of learning and memory may be gleaned from animals that have special characteristics not found in other species. Tardigrades, also known as "water bears," are microscopic eight-legged animals that live in various aquatic and terrestrial environments. They are known for their resilience to extreme conditions because of their ability to enter a cryptobiotic "tun" state during which they turn off their metabolism. Thus, tardigrades present an ideal model to study the metabolic requirements for memory storage. However, there is no prior research on tardigrade learning and memory. The purpose of this study was to demonstrate aversive conditioning in a tardigrade species, Dactylobiotus dispar. Associative learning was confirmed by numerous control conditions (unconditioned stimulus [US] only, conditional stimulus [CS] only, backward pairing, random pairing). Short-term memories were formed after a single pairing of the CS and US. This research introduces an important new animal model to the study of the neurobiology of aversive conditioning with important ramifications for understanding the metabolic influences on learning and memory. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons.

N-methyl-d-aspartate receptors (NMDARs) are glutamatergic receptors that take part in excitatory synaptic transmission and drive functional and structural neuronal plasticity, including activity-dependent changes in dendritic morphology. Forebrain NMDARs contribute to neuronal plasticity in at least two ways: through calcium-mediated processes or via direct intracellular postsynaptic signaling. Both properties are regulated by the GluN2 subunits. However, the separate contributions of these properties to the regulation of dendritic morphology are unknown. We created transgenic mice that express chimeric GluN2 subunits and examined the impact on pyramidal cell dendritic morphology in hippocampal region CA1. Golgi-Cox impregnation and transgenic expression of green fluorescent protein were employed to visualize dendritic arbors. In adult mice with a predominantly native GluN2A background, overexpression of the GluN2B carboxy terminus increased the total path of the dendritic arbor without affecting branch number or tortuosity. Overexpressing the amino terminus and transmembrane domains of GluN2B had little effect. It may be inferred from these results that NMDAR-dependent intracellular signaling regulates dendritic morphology of hippocampal pyramidal cells more so than calcium conductance dynamics. The findings add to the understanding of NMDAR-mediated signaling in hippocampal neurons and support re-investigation of the molecular underpinnings of NMDAR involvement in postnatal dendrite maturation.

A Modified Barnes Maze for Juvenile Rats.

To better understand neural codes for spatial navigation and to address cognitive development questions, the neurobiology of postnatal hippocampal development is receiving increased attention. While the Morris Water Maze is the gold standard for assessing hippocampal integrity, potential confounds can be difficult to control for in juvenile rodents (around three weeks of age, when spatial navigation ability first emerges) and this wet maze is not amenable to electrophysiological recording. A dry maze alternative with minimal training, like the Barnes Maze adapted for juvenile rats, can help overcome these obstacles. This paper describes in detail the experimental procedure and data analyses for the adapted Barnes maze for juvenile animals.

Removal of area CA3 from hippocampal slices induces postsynaptic plasticity at Schaffer collateral synapses that normalizes CA1 pyramidal cell discharge.

Neural networks that undergo acute insults display remarkable reorganization. This injury related plasticity is thought to permit recovery of function in the face of damage that cannot be reversed. Previously, an increase in the transmission strength at Schaffer collateral to CA1 pyramidal cell synapses was observed after long-term activity reduction in organotypic hippocampal slices. Here we report that, following acute preparation of adult rat hippocampal slices and surgical removal of area CA3, input to area CA1 was reduced and Schaffer collateral synapses underwent functional strengthening. This increase in synaptic strength was limited to Schaffer collateral inputs (no alteration to temporoammonic synapses) and acted to normalize postsynaptic discharge, supporting a homeostatic or compensatory response. Short-term plasticity was not altered, but an increase in immunohistochemical labeling of GluA1 subunits was observed in the stratum radiatum (but not stratum moleculare), suggesting increased numbers of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and a postsynaptic locus of expression. Combined, these data support the idea that, in response to the reduction in presynaptic activity caused by removal of area CA3, Schaffer collateral synapses undergo a relatively rapid increase in functional efficacy likely supported by insertion of more AMPARs, which maintains postsynaptic excitability in CA1 pyramidal neurons. This novel fast compensatory plasticity exhibits properties that would allow it to maintain optimal network activity levels in the hippocampus, a brain structure lauded for its ongoing experience-dependent malleability.

Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning.

N-methyl-D-aspartate receptors (NMDARs) act as molecular coincidence detectors and allow for association or dissociation between pre- and postsynaptic neurons. NMDA receptors are central to remodeling of synaptic connections during postnatal development and associative learning abilities in adults. The ability to remodel neural networks is altered during postnatal development, possibly due to a change in the composition of NMDARs. That is, as forebrain systems (and cerebellum) develop, synaptic NR2B-containing NMDARs (NR2B-NMDARs) are replaced by NR2A-containing NMDARs (NR2A-NMDARs) and NR2B-NMDARs move to extrasynaptic sites. During the initial phase of the switch, synapses contain both NR2A- and NR2B-NMDARs and both long-term potentiation and long-term depression are enhanced. As NMDAR subunit expression decreases and NR2A-NMDARs come to predominate in the synapse, channel function and synaptic plasticity are reduced, and remodeling ability dissipates. The end result is a balance of plasticity and stability that is optimal for information processing and storage. Associative learning abilities involving different sensory modalities emerge sequentially, in accordance with synaptic maturation in related cortical and underlying brain structures. Thus, developmental alterations in NMDAR composition that occur at different ages in various brain structures may explain the protracted nature of the maturation of various associative learning abilities.