Robert W. Stackman

Small Conductance Ca2+-Activated K+ Channel Knock-Out Mice Reveal the Identity of Calcium-Dependent Afterhyperpolarization Currents

Action potentials in many central neurons are followed by a prolonged afterhyperpolarization (AHP) that influences firing frequency and affects neuronal integration. In hippocampal CA1 pyramidal neurons, the current ascribed to the AHP (IAHP) has three kinetic components. The IfastAHP is predominantly attributable to voltage-dependent K+ channels, whereas Ca2+-dependent and voltage-independent K+channels contribute to the ImediumAHP (ImAHP) and IslowAHP (IsAHP). Apamin, which selectively suppresses a component of the mAHP, increases neuronal excitability and facilitates the induction of synaptic plasticity at Schaffer collateral synapses and hippocampal-dependent learning. The Ca2+-dependent components of the AHP have been attributed to the activity of small conductance Ca2+-activated K+ (SK) channels. Examination of transgenic mice, each lacking one of the three SK channel genes expressed in the CNS, reveals that mice without the SK2 subunit completely lack the apamin-sensitive component of the ImAHP in CA1 neurons, whereas the IsAHP is not different in any of the SK transgenic mice. In each of the transgenic lines, the expression levels of the remaining SK genes are not changed. The results demonstrate that only SK2 channels are necessary for the ImAHP, and none of the SK channels underlie the IsAHP.

Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment.

Alzheimers disease (AD) is characterized by cognitive decline and deposition of beta-amyloid (Abeta) plaques in cortex and hippocampus. A transgenic mouse AD model (Tg2576) that overexpresses a mutant form of human Abeta precursor protein exhibits age-related cognitive deficits, Abeta plaque deposition, and oxidative damage in the brain. We tested the ability of Ginkgo biloba, a flavonoid-rich antioxidant, to antagonize the age-related behavioral impairment and neuropathology exhibited by Tg2576 mice. At 8 months of age, 16 female Tg2576 and 15 female wild-type (wt) littermate mice were given ad lib access to tap water or Ginkgo biloba (70 mg/kg/day in water). After 6 months of treatment, all mice received Morris water maze training (4 trials/day for 10 days) to assess hippocampal dependent spatial learning. All mice received a 60-s probe test of spatial memory retention 24 h after the 40th trial. Untreated Tg2576 mice exhibited a spatial learning impairment, relative to wt mice, while Ginkgo biloba-treated Tg2576 mice exhibited spatial memory retention comparable to wt during the probe test. Spatial learning was not different between Ginkgo biloba-treated and untreated wt mice. There were no group differences in learning to swim to a visible platform. Soluble Abeta and hippocampal Abeta plaque burden did not differ between the Tg2576 groups. Brain levels of protein carbonyls were paradoxically elevated in Ginkgo biloba-treated mice. These data indicate that chronic Ginkgo biloba treatment can block an age-dependent decline in spatial cognition without altering Abeta levels and without suppressing protein oxidation in a transgenic mouse model of AD.

Small-Conductance Ca2+-Activated K+ Channel Type 2 (SK2) Modulates Hippocampal Learning, Memory, and Synaptic Plasticity

Apamin-sensitive, small-conductance, Ca2+-activated K+ channels (SK channels) modulate neuronal excitability in CA1 neurons. Blocking all SK channel subtypes with apamin facilitates the induction of hippocampal synaptic plasticity and enhances hippocampal learning. In CA1 dendrites, SK channels are activated by Ca2+ through NMDA receptors and restrict glutamate-mediated EPSPs. Studies of SK channel knock-out mice reveal that of the three apamin-sensitive SK channel subunits (SK1–SK3), only SK2 subunits are necessary for the apamin-sensitive currents in CA1 hippocampal neurons. To determine the specific influence of SK2 channels on hippocampal synaptic plasticity, learning, and memory, we used gene targeting through homologous recombination in embryonic stem cells to generate transgenic mice that overexpress SK2 subunits by 10-fold (SK2+/T). In these mice, the apamin-sensitive current in CA1 neurons was increased by approximately fourfold, relative to wild-type (WT) littermates. In addition, the amplitude of synaptically evoked EPSPs recorded from SK2+/T CA1 neurons increased twice as much in response to SK channel blockade relative to EPSPs recorded from WT CA1 neurons. Consistent with this, SK2 overexpression reduced long-term potentiation after high-frequency stimulation compared with WT littermates and severely impaired learning in both hippocampus- and amygdala-dependent tasks. We conclude that SK2 channels regulate hippocampal synaptic plasticity and play a critical role in modulating mechanisms of learning and memory.

Processing the head direction cell signal: A review and commentary

Animals require information about their location and directional heading in order to navigate. Directional information is provided by a population of cells in the postsubiculum and the anterior thalamic nuclei that encode a very accurate, continual representation of the animals directional heading in the horizontal plane, which is independent of the animals location. Recent studies indicate that this signal 1) arises either in the anterior thalamic nuclei or in structures upstream from it; 2) is not dependent on an intact hippocampus; 3) receives sensory inputs from both idiothetic and landmark systems; and 4) correlates well with the animals behavior in a spatial reference memory task. Furthermore, HD cells in the anterior thalamic nuclei appear to encode what the animals directional heading will be about 40 ms in the future, while HD cells in the postsubiculum encode the animals current directional heading. Both the electrophysiological and anatomical data suggest that the anterior thalamic nuclei and/or the lateral mammillary nuclei may be the sites of convergence for spatial information derived from landmarks and internally-generated cues. Current evidence also indicates that the vestibular system plays a crucial role in the generation of the HD cell signal. However, the notion that the vestibular system is the sole contributor to the signal generator is difficult to reconcile with several findings; these latter findings are better accounted for with a motor efference copy signal.

Stability of Spatial Working Memory across the Estrous Cycle of Long–Evans Rats

In the adult rat, hippocampal dendritic synaptic connectivity in region CA1 fluctuates across the estrous cycle. This study examined the potential functional impact of such fluctuations on spatial working memory in regularly cycling Long-Evans rats. Rats were trained in a delayed non-match-to-sample radial-arm maze task and performance was monitored across the estrous cycle. There were no significant alterations in the acquisition or performance of the working memory task across the estrous cycle, with 1- or 4-h delays imposed between training and testing sessions. However, rats performed the task significantly more slowly on proestrus than on any other estrous cycle day under both delay conditions. These results indicate that while working memory remains stable, sensorimotor or motivational aspects of the performance of this radial-arm maze task may vary across the estrous cycle.

The rodent hippocampus is essential for nonspatial object memory.

Elucidating the role of the rodent hippocampus in object recognition memory is critical for establishing the appropriateness of rodents as models of human memory and for their use in the development of memory disorder treatments. In mammals, spatial memory and nonspatial memory depend upon the hippocampus and associated medial temporal lobe (MTL) structures. Although well established in humans, the role of the rodent hippocampus in object memory remains highly debated due to conflicting findings across temporary and permanent hippocampal lesion studies and evidence that the perirhinal cortex may support object memory. In the current studies, we used intrahippocampal muscimol microinfusions to transiently inactivate the male C57BL/6J mouse hippocampus at distinct stages during the novel object recognition (NOR) task: during object memory encoding and consolidation, just consolidation, and/or retrieval. We also assessed the effect of temporary hippocampal inactivation when objects were presented in different contexts, thus eliminating the spatial or contextual components of the task. Lastly, we assessed extracellular dorsal hippocampal glutamate efflux and firing properties of hippocampal neurons while mice performed the NOR task. Our results reveal a clear and compelling role of the rodent hippocampus in nonspatial object memory.

Chronic dietary α-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice

Oxidative stress may play a key role in Alzheimers disease (AD) neuropathology. Here, the effects of the antioxidant, α-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble β-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting β-amyloid levels or plaque deposition.

Rats with lesions of the vestibular system require a visual landmark for spatial navigation

The role of the vestibular system in acquisition and performance of a spatial navigation task was examined in rats. Male Long-Evans rats received sham or bilateral sodium arsanilate-induced vestibular lesions. After postoperative recovery, under partial water-deprivation, rats were trained (16 trials/day) to find a water reward in one corner of a black square enclosure. A cue card fixed to one wall of the enclosure served as a stable landmark cue. The orientation of the rat at the start of each trial was pseudo-randomized such that the task could not be solved by an egocentric response strategy. Rats with vestibular lesions acquired the task in fewer trials than the sham treated control rats. Vestibular lesions did not influence the motivation or motor function necessary to perform the task. Performance of sham rats was maintained during probe trials in which the cue card was removed from the enclosure, while lesioned rats were markedly impaired. Rotation of the cue card (+/-90 degrees ) caused an equivalent shift in corner choice behavior of the lesioned rats. However, sham rats often disregarded the rotated cue card and made place responses. These results suggest that the vestibular lesions disrupt idiothetic navigation or path integration and render navigational behavior critically dependent upon external landmarks. These results are consistent with the navigational abilities of humans with bilateral vestibular dysfunction.

Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats

Background Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders. Objective We tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs). Methods and Results The Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [3H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity. Conclusions Developmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.

The role of serotonin 5-HT2A receptors in memory and cognition

Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders.