Nonna A. Otmakhova

Dopamine Selectively Inhibits the Direct Cortical Pathway to the CA1 Hippocampal Region

The perforant path input (pp) is a major direct source of specific sensory information for the CA1 hippocampal region. The termination area of this pathway, the stratum lacunosum-moleculare, has the highest concentration of dopamine receptors in the hippocampus. We have examined the properties of the pp input and its modulation by dopamine. The input is glutamatergic and has a larger NMDA component than the Schaffer collateral (sc) input. Dopamine strongly inhibits the response to pp stimulation (IC50 ∼3 μm) but not the response to sc stimulation. Dopamine reduces both the NMDA and AMPA components of transmission at the pp and increases paired-pulse facilitation. In the sc, the NMDA component but not the AMPA component is decreased, and paired-pulse facilitation is not affected. The effect of dopamine on the pp does not depend on GABAA inhibition but is reduced by the antagonists of both D1 and D2 families of dopamine receptors. The effect is not completely blocked by the combination of D1 and D2 antagonists, but is completely blocked by the atypical neuroleptic clozapine. Our results provide the first evidence for strong dopaminergic control of transmission in the perforant path. By inhibiting this pathway, dopamine hyperfunction and/or NMDA hypofunction abnormalities implicated in schizophrenia may isolate CA1 from its main source of sensory information.

Pathway-specific properties of AMPA and NMDA-mediated transmission in CA1 hippocampal pyramidal cells.

CA1 pyramidal cells receive glutamatergic input from the entorhinal cortex through the perforant path (PP) and from CA3 through Schaffer collaterals (SC). The PP input terminates in the stratum lacunosum moleculare ∼300 μm from the cell body, whereas SC synapses have a more proximal location in the stratum radiatum. We compared the properties of AMPA- and NMDA-mediated transmission at these two inputs. The AMPA-mediated components have linear voltage dependence in both inputs. The reversal potential in the PP is only slightly more positive than in the SC, indicating that distal membrane voltage could be effectively set. The NMDA-mediated responses in the two pathways, however, are very different. The PP exhibits inward rectification, as evidenced by very low outward currents. The rectification persists in the absence of extracellular Mg2+. It cannot be attributed to clamping problems, because large outward AMPA currents can be observed even when conditions are modified to have the AMPA currents kinetically match the NMDA currents. Thus, it appears that the PP NMDA channels have novel properties. A second difference between the PP and SC pathways is that the PP has a larger NMDA/AMPA charge ratio. This difference could be observed under many conditions, including block of all voltage-dependent conductances and elimination of the negative resistance of NMDA channels by removing extracellular Mg2+. The difference in ratio thus cannot be attributed to regenerative currents. The higher NMDA component of the distal PP synapses could help to make these synapses more powerful under depolarizing conditions.

A Thalamo-Hippocampal-Ventral Tegmental Area Loop May Produce the Positive Feedback that Underlies the Psychotic Break in Schizophrenia

The N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia is based on the ability of NMDAR antagonists to produce many symptoms of the disease. Recent work in rats shows that NMDAR antagonist works synergistically with dopamine to produce delta frequency bursting in the thalamus. This finding, together with other results in the literature, suggests a mechanism for the sudden onset of schizophrenia. Among the thalamic nuclei most activated by NMDAR antagonist is the nucleus reuniens. This nucleus excites the cornu ammonis area 1 (CA1) region of the hippocampus. Experiments indicate that such activation can lead to excitation of dopaminergic cells of the ventral tegmental area by a polysynaptic pathway. The resulting elevation of dopamine in the thalamus will enhance thalamic bursting, thereby creating a loop with the potential for positive feedback. We show through computer simulations that in individuals with susceptibility to schizophrenia (e.g., because of partially compromised NMDAR function), an event that stimulates the dopamine system, such as stress, can cause the system to reach the threshold for thalamic bursting. When this occurs, positive feedback in the loop will cause all components to become highly active and to remain active after the triggering stimulus is removed. This is a physiologically specific hypothesis for the sudden and lasting transition that underlies the psychotic break in schizophrenia. Furthermore, the model provides an explanation for the observed selective activation of the CA1 hippocampal region in schizophrenia. The model also predicts an increase of basal activity in the dopamine system and thalamus; the relevant evidence is reviewed.

ReviewA Thalamo-Hippocampal-Ventral Tegmental Area Loop May Produce the Positive Feedback that Underlies the Psychotic Break in Schizophrenia

The N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia is based on the ability of NMDAR antagonists to produce many symptoms of the disease. Recent work in rats shows that NMDAR antagonist works synergistically with dopamine to produce delta frequency bursting in the thalamus. This finding, together with other results in the literature, suggests a mechanism for the sudden onset of schizophrenia. Among the thalamic nuclei most activated by NMDAR antagonist is the nucleus reuniens. This nucleus excites the cornu ammonis area 1 (CA1) region of the hippocampus. Experiments indicate that such activation can lead to excitation of dopaminergic cells of the ventral tegmental area by a polysynaptic pathway. The resulting elevation of dopamine in the thalamus will enhance thalamic bursting, thereby creating a loop with the potential for positive feedback. We show through computer simulations that in individuals with susceptibility to schizophrenia (e.g., because of partially compromised NMDAR function), an event that stimulates the dopamine system, such as stress, can cause the system to reach the threshold for thalamic bursting. When this occurs, positive feedback in the loop will cause all components to become highly active and to remain active after the triggering stimulus is removed. This is a physiologically specific hypothesis for the sudden and lasting transition that underlies the psychotic break in schizophrenia. Furthermore, the model provides an explanation for the observed selective activation of the CA1 hippocampal region in schizophrenia. The model also predicts an increase of basal activity in the dopamine system and thalamus; the relevant evidence is reviewed.

The Hippocampal-VTA Loop: The Role of Novelty and Motivation in Controlling the Entry of Information into Long-Term Memory

The role of dopamine has been strongly implicated in reward processes, but recent work shows an additional role as a signal that promotes the stable incorporation of novel information into long-term hippocampal memory. Indeed, dopamine neurons, in addition to being activated by reward, can be activated by novelty in the absence of reward. The computation of novelty is thought to occur in the hippocampus and is carried to the dopamine cells of the VTA through a polysynaptic pathway. Although a picture of novelty-dependent processes in the VTA and hippocampus is beginning to emerge, many aspects of the process remain unclear. Here, we will consider several issues: (1) What is relationship of novelty signals coming to the VTA from the superior colliculus, as compared to those that come from the hippocampus? (2) Can dopamine released by a reward enhance the learning of novel information? (3) Is there an interaction between motivational signals and hippocampal novelty signals? (4) What are the properties of the axons that generate dopamine release in the hippocampus? We close with a discussion of some of the outstanding open issues in this field.

The Phases of LTP: The New Complexities

The work begun by John Sarvey on the biochemical processes involved in synaptic plasticity has progressed rapidly. The LTP field is now blessed with a great deal of data showing how the different phases of LTP and the synaptic weakening processes are affected by pharmacological and genetic perturbations. There is the feeling in the memory field that the cast of characters involved in LTP has been largely identified. These include second messenger cascades, kinases, phosphatases, channels, structural proteins, a vesicle delivery system, regulators of gene transcription and translation, and mediators of synaptic growth. The challenge ahead is to understand how this cast works together to make the play memorable.

Memories of John Lisman

John Lisman had a passionate connection with life, art and science. He lived his life till the end with enthusiasm and energy, passing away on October 20, 2017. John said many times that he did not understand how people could retire from science—he personally would not know how to live without intellectually challenging himself every day. When he found out that he had cancer, and that his expected life span was “short or very short” he announced that he and his family were “not into grieving.” So it was business as usual. He just added the challenge of understanding cancer and treatment options to his list of challenges. He worked harder than ever, while making more time for his family and friends in the last months.