José Ambros-Ingerson

Enhancement by an Ampakine of Memory Encoding in Humans

Acentrally active drug that enhances AMPA receptor-mediated currents was tested for its effects on memory in humans. Evidence for a positive influence on encoding was obtained in four tests: (i) visual associations, (ii) recognition of odors, (iii) acquisition of a visuospatial maze, and (iv) location and identity of playing cards. The drug did not improve scores in a task requiring cued recall of verbal information. The selectivity of drug effects on memory was confirmed using tests of visual recognition, motor performance, and general intellectual functioning. These results suggest that positive modulators of AMPA receptors selectively improve at least some aspects of memory.

Evidence That a Positive Modulator of AMPA-Type Glutamate Receptors Improves Delayed Recall in Aged Humans

Elderly subjects (65-76 years) were tested for recall of nonsense syllables prior to and after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine (CX516), a centrally active drug that enhances currents mediated by AMPA-type glutamate receptors. A significant and positive drug effect was found for delayed (5 min) recall at 75 min posttreatment; average scores for the highest dose group were more than twofold greater than for the placebo group. The drug had no evident influence on heart rate or self-assessment of several psychological variables.

A centrally active drug that modulates AMPA receptor gated currents.

Systemic administration of the drug 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP) has been reported to enhance monosynaptic responses in the hippocampus in vivo and to improve spatial and olfactory memory in rats. The drugs mechanism of action was investigated in the present study using membrane patches excised from cultured hippocampal slices. The decay time of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor mediated inward currents was greatly increased by 1-BCP in a concentration dependent and reversible fashion; peak current was also enhanced but to a lesser degree. In vitro slice experiments indicated that the drug has parallel effects on the field EPSP. It is concluded that 1-BCP is a centrally active modulator of the AMPA receptor.

Effects of a centrally active benzoylpiperidine drug on α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor kinetics

A newly developed benzoylpiperidine drug that increases the size of fast, excitatory synaptic responses was examined for its effects on the kinetic properties of α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid-type glutamate receptors. When long pulses of glutamate were applied to excised hippocampal patches of the rat, the compound [1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20] caused an approximately 15-fold reduction in the rate at which responses desensitized and a similar size increase in steady-state currents. In experiments using 1-ms glutamate pulses, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 prolonged response deactivation by a factor of about four and greatly reduced the depression in the second response when two consecutive glutamate pulses were given. Two types of equilibrium binding assays indicated that 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 causes a measurable increase in the affinity of α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptors; the ec50 values for this effect were similar to those obtained in excised patch studies. The actions of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 on physiology and ligand binding could be adequately reproduced in a receptor model by slowing the rate of desensitization and increasing the affinity of the sensitized states. The biochemical and physiological effects of benzoylpiperidine compounds were qualitatively different from those obtained with cyclothiazide, although both types of drug increased α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor-mediated synaptic responses. Moreover, interactions between the drugs were at most only partially competitive; α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptors may thus have multiple modulatory sites with distinct drug preferences and different effects on receptor kinetics.

Derivation of encoding characteristics of layer ii cerebral cortex

Computer simulations of layers I and II of pirifonn (olfactory) cortex indicate that this biological network can generate a series of distinct output responses to individual stimuli, such that different responses encode different levels of information about a stimulus. In particular, after learning a set of stimuli modeled after distinct groups of odors, the simulated networks initial response to a cue indicates only its group or category, whereas subsequent responses to the same stimulus successively subdivide the group into increasingly specific encoding of the individual cue. These sequences of responses amount to an automated organization of perceptual memories according to both their similarities and differences, facilitating transfer of learned information to novel stimuli without loss of specific information about exceptions. Human recognition performance robustly exhibits such multiple levels: a given object can be identified as a vehicle, as an automobile, or as a Mustang. The findings reported here suggest that a function as apparently complex as hierarchical recognition memory, which seems suggestive of higher cognitive processes, may be a fundamental intrinsic property of the operation of this single cortical cell layer in response to naturally-occurring inputs to the structure. We offer the hypothesis that the network function of superficial cerebral conical layers may simultaneously acquire and hierarchically organize information about the similarities and differences among perceived stimuli. Experimental manipulation of the simulation has generated hypotheses of direct links between the values of specific biological features and particular attributes of behavior, generating testable physiological and behavioral predictions.

Psychological effects of a drug that facilitates brain Ampa receptors

The effects of l-(quinovalin-6-ylcarbonyl)piperidine (CX516), a centrally active compound that facilitates AMPA receptor-mediated synaptic responses, were tested in human subjects. Separate tests of delayed recall were given prior to and nearly 3 h after administration of placebo (n = 12) or drug (n = 36). Control subjects exhibited poorer performance in the second session than in the first while subjects given 600–1200 mg of the drug did not. There were no pre- vs post-treatment differences in immediate recall in either group. The drug did not reliably affect self-assessment scores for any of several psychological variables but did disrupt the normally present correlations for within-subject changes in the variables. These results suggest that AMPA receptor modulators may (1) improve memory under some circumstances and (2) produce psychological effects that are subtle or not related to specific mood states.

Cyclothiazide decreases (3H)AMPA binding to rat brain membranes: evidence that AMPA receptor desensitization increases agonist affinity

The effects of cyclothiazide, a drug which blocks AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor desensitization, were tested on binding of [3H]AMPA to rat brain membranes. Cyclothiazide reduced [3H]AMPA binding by lowering the apparent affinity of the AMPA receptor. The magnitude of the decrease was temperature dependent and greater for membrane-bound than for solubilized receptors. These data provide evidence that desensitization increases the affinity of the AMPA receptor for agonists and indicate that a significant percentage of AMPA receptors in conventional equilibrium binding assays are in a desensitized state.

Stoichiometries of AMPA receptor subunit mRNAs in rat brain fall into discrete categories

In situ hybridization was used to estimate the relative concentrations of mRNAs encoding different subunits (GluR1‐4) of α‐amino 3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA)‐type glutamate receptors in rat brain and to test the hypothesis that within‐region expression profiles reflect a limited number of recurring patterns. Fractional subunit mRNA concentrations were calculated for 33 brain regions, and cluster analysis methods were applied to test for statistically meaningful groupings in the data. Four relatively homogeneous classes were identified and designated as AMPA receptor (AR) categories, numbered according to dominant subunit mRNAs. The AR‐1 class (47% GluR1 mRNA) was expressed by structures near the mesodiencephalic border, including basal ganglia‐related areas. The AR‐2 class (57% GluR2 mRNA) was expressed in cortex and tectum. The AR‐1,2 class (31% GluR1, 45% GluR2) was found in the largest number of regions, including such dissimilar cell fields as hippocampus and substantia nigra pars compacta. The AR‐2,3 grouping (33% GluR2, 31% GluR3) was associated with the sensory relay and reticular thalamic nuclei. It is suggested that AR‐1,2 and AR‐2, the most closely related categories in clustering space, are largely telencephalic receptors with the former predominant in the subcortex and the latter in the cortex. The AR‐2,3 class is associated with ascending sensory stations, whereas AR‐1 appears to include several smaller categories expressed by specialized systems. If the balance of subunit mRNAs is reflected at the protein level, then the present data suggest that forebrain AMPA‐type glutamate receptors can be classified into a limited number of recurring types. J. Comp. Neurol. 385:491–502, 1997.

Waveform analysis suggests that LTP alters the kinetics of synaptic receptor channels

The waveform of an isolated excitatory monosynaptic response reflects the kinetics of transmitter release, the kinetics of synaptic receptor channels and the filtering properties of neurons. Results reported here indicate that long-term potentiation (LTP) causes correlated decreases in the rise time and decay time constant of synaptic potentials recorded in hippocampal slices in which inhibitory currents and post-synaptic spiking were suppressed. Statistical comparisons of waveforms revealed that the distortions introduced by LTP could be corrected by stretching the time-scale of potentiated responses according to the percent change in the decay time constant. The LTP associated decrease in the decay time constant also obtained in slices from immature hippocampus which contain spines and dendrites greatly simplified from those of the adult. Hence, filtering properties of spines are not likely involved in the effect. Paired-pulse facilitation (PPF), a transient increase in transmitter release, did not reproduce the waveform effects of LTP but did cause a slight leftward shift of the response. These results suggest that LTP modifies the kinetics of receptor channels, and that PPF accelerates release.

Short‐term reverberant memory model of hippocampal field CA3

Synaptic plasticity mechanisms for associative learning require near‐simultaneous pairs of inputs to target cells. Sensory cues encountered behaviorally, however, are typically staggered in time, implying the need for active short‐term memory traces of antecedent cues. The dense recurrent connectivity within regions of hippocampal field CA3 is suggestive of the kind of re‐entrant network that could subserve this kind of “holding” memory. Consequently, we have investigated whether an abstract model of this region incorporating its major anatomical and physiological features could function as a reverberatory memory network. The continuous‐time model describes the behavior of highly connected groups of CA3 pyramidal cells, or “patches,” in response to brief, rhythmic, sensory stimulation. Time constants for excitatory and inhibitory postsynaptic potentials and axonal transmission delays for local and distal connections were estimated from empirical data. When the inhibitory units in these patches were connected to an oscillator intended to model the theta wave activity of the medial septum, the network entered reverberatory states and maintained second‐long memory traces of the cortical input, after which it lost its coherent behavior. Noise analysis indicated that the networks operation was moderately resistant to random fluctuations proportional to patch activity. These results suggest that field CA3 could function as a holding memory that assists the integration of disjoint stimuli found in innumerable associative tasks, and that the duration of its coherent operation might determine the temporal limits in their performance. Hippocampus 1997;7:656–665. © 1997 Wiley‐Liss, Inc.