Psychiatric Annals

Feature Article 

Impact of the Alpha-7 Nicotinic Acetylcholine Receptor on Long-Term Potentiation within the Hippocampus: Implications in Schizophrenia

Candace Jones, BS

Abstract

Schizophrenia is a debilitating psychiatric disorder associated with progressive cognitive decline across perception, social and affective processes, and memory. The alpha-7 nicotinic acetylcholine receptor (a7 nAChR) is implicated in the cognitive pathophysiology of schizophrenia. This receptor specifically affects memory by facilitating long-term potentiation (LTP) within the hippocampus. This article reviews the role of the a7 nAChR in enhancement of LTP via its impact on hippocampal gamma-aminobutyric acid (GABA)-ergic and glutamatergic pathways. Future therapeutic implications of a7 nAChR in improvement of cognitive impairment in schizophrenia are also discussed. [Psychiatr Ann. 2018;48(7):345–348.]

Abstract

Schizophrenia is a debilitating psychiatric disorder associated with progressive cognitive decline across perception, social and affective processes, and memory. The alpha-7 nicotinic acetylcholine receptor (a7 nAChR) is implicated in the cognitive pathophysiology of schizophrenia. This receptor specifically affects memory by facilitating long-term potentiation (LTP) within the hippocampus. This article reviews the role of the a7 nAChR in enhancement of LTP via its impact on hippocampal gamma-aminobutyric acid (GABA)-ergic and glutamatergic pathways. Future therapeutic implications of a7 nAChR in improvement of cognitive impairment in schizophrenia are also discussed. [Psychiatr Ann. 2018;48(7):345–348.]

Cognitive impairment is a core component of schizophrenia. Deficits in memory, executive functioning, and social and affective processing are well established in schizophrenia symptomology.1 Yet, the underlying neurophysiology of these cognitive deficits is not well understood and remains a key area of investigation in schizophrenia research. Current antipsychotic drugs, such as olanzapine, target the positive symptoms of schizophrenia by invoking or dampening the signals of dopaminergic, serotoninergic, and other pathways within the central nervous system (CNS).2 However, these medications have little effect on the cognitive decline or negative symptoms in patients with schizophrenia. This ineffectiveness has led scientists to explore other receptor targets within the CNS.

The nicotinic acetylcholine receptor (nAChR) is one pharmacological target that has come into focus. It is well established that people with schizophrenia have higher rates of smoking than the general population due to the therapeutic effects of nicotine.3 Researchers have demonstrated that activation of specific nAChRs within the CNS mediate pro-cognitive effects across multiple domains, including perception, social and affective processes, working memory, and long-term memory, in patients with schizophrenia.3 Multiple nicotinic receptor subtypes have been implicated in contributing to the cognitive decline in schizophrenia. One of these subtypes is the alpha-7 (a7) nAChR, which is found in multiple regions of the brain involved with cognition, including the hippocampus, cortex, and subcortical regions.4 Postmortem studies of people with schizophrenia have demonstrated less a7 nAChR expression within the hippocampus, a region involved with memory.3 In addition, a recent trial of a7 nAChR agonists and positive allosteric modulators supports improvement of hippocampal working memory and long-term memory via a7 nAChR in patients with schizophrenia.4

Multiple studies5–7 have used electrophysiologic recordings to monitor the impact of a7 nAChR on neuronal plasticity via enhancement of long-term potentiation (LTP), which is the basis of memory within the hippocampus. The a7 nAChR is widely distributed throughout the dentate gyrus, cornu ammonis (CA) 3, and CA1 regions of the hippocampus.6 a7 nAChRs can alter neurotransmission presynaptically via regulation of neurotransmitter release or postsynaptically via mediation of the electrical response during cholinergic transmission.5 Alteration of episodic memory, including spatial and verbal, working memory, and long-term memory, have all been implicated in schizophrenia.2 This article highlights the latest research on a7 nAChR's role in enhancement of hippocampal LTP via glutamatergic pathways, GABAergic pathways, and facilitation of these tracks. Clinical implications in schizophrenia are also discussed.

Alteration of LTP via Glutamatergic Pathways

LTP describes the process of strengthening synapses based on repetitive stimulation of a postsynaptic neuron.8 This process underlies formation of long-term memories and is believed to be impaired in schizophrenia.6 One of the mechanisms underlying hippocampal LTP involves the stimulation of CA1 pyramidal neurons by CA3 pyramidal neurons via Schafer collaterals, generating excitatory postsynaptic potentials (EPSPs) via AMPA glutamate receptors.8 Tetanic stimulation leads to further depolarization of the CA1 membrane, causing the opening of the metabotropic glutamate receptor N-methyl-D-aspartate (NMDA). Activation of the NMDA receptor leads to strengthening of the synapse via a cascade, resulting in phosphorylation and upregulation of AMPA receptors.8 This is “early” LTP. Late “LTP” involves activating specific genes and proteins via a cascade with calcium as a second messenger.3 This process is thought to be abnormal in patients with schizophrenia.6

Within the hippocampus, a7 nAChRs are located on CA1 and CA3 cells and enhance facilitation of LTP.5 These receptors are permeable to calcium and when activated, calcium levels increase within the CA1 and CA3 pyramidal neurons.5 Thus, a7 nACh receptors facilitate synapse strengthening presynaptically and postsynaptically. This leads to enhancement of glutamate release and postsynaptic depolarization, enabling LTP to occur. In addition, a7 nAChR affects both early LTP through increased calcium and late LTP via cascades activated by Ca2+ as a second messenger.9 Cheng and Yakel7 demonstrated that a7 nAChR activation in CA3 neurons leads to increases in CA1 EPSP amplitudes that continue for 5 to 10 minutes after removal of the agonist. Enhancement of LTP via nAChR is dependent on synchronized timing of stimulation of glutamatergic currents and a7 nAChR. Outside of these specific time frames, LTP will not occur.7

Schizophrenia involves the complex interactions of multiple genes and the environment. The underlying neuromechanisms leading to schizophrenia development in one case can significantly differ from others. This concept includes variance in a7 nAChR expression, timing of stimulation, and to what degree memory and other cognitive domains are affected. Freund et al.9 created knockout mouse models of the Chrna7 gene, which encodes a7 nAChR, in various genetic backgrounds. These included homozygous and heterozygous a7-deletion CH3 mice that express high nAChR levels at baseline and homozygous a7-deletion C57/B16 mice, which express fewer nAChRs at baseline. Homozygous CH3 mice had significantly impaired hippocampal LTP via glutamatergic NMDA receptors at CA1 synapses; however, heterozygous CH3 mice continued to have hippocampal synaptic plasticity via LTP. In contrast to the homozygous CH3 mice, homozygous C57/B16 mice had normal LTP, similar to wild-type controls, indicating that nAchR7 plays an insignificant role in LTP in mice of this genetic background. In schizophrenia, reductions of Chrna7 have been found in tissue samples from the hippocampus, a brain region that usually has the highest Chrna7 expression.4 Based on the findings by Freund et al.,9 one theory underlying memory impairment in schizophrenia is a negative correlation between high levels of nAChR expression and cognition.

Alteration of LTP via GABA-ergic Pathways

GABAergic interneurons within the hippocampus also express presynaptic a7 nAChR receptors. These receptors in the CA1 pyramidal region enhance excitatory glutamatergic signals, leading to LTP.10 Traditionally, these GABAergic neurons were believed to suppress excitatory glutamatergic signaling. However, these interneurons recently have been found to both depress and facilitate glutamatergic signaling, with a result of LTP or long-term depression.10 Within the hippocampus, multiple types of GABAergic receptors exist. These include self-innervating GABA subtypes, GABA neurons subtypes that will only synapse on different subtypes, and GABA neurons interconnected by both chemical and electrical synapses.11 Similarly to glutamatergic transmission, the outcomes of GABAergic signaling are dependent on timing between a7 nAChR activation and presynaptic stimulation of specific GABA receptor subtypes.

This facilitation of LTP via GABAergic pathways is supported by research from Townsend et al.6 Using FRM-17848, an a7 nAChR agonist, they demonstrated that FRM-17848 enhances LTP in rat hippocampal brain slices within a narrow concentration range.5 This same concentration stimulated specific GABAergic interneurons. Thus, this study implicates the potential of a7 nAChr agonists to increase synaptic plasticity and resulting cognitive enhancement via its effects on GABA receptors, not just glutamate receptors. This apparent paradox between GABAergic signaling and excitatory output has been theorized to be related to multiple neuromechanisms, including feed-forward inhibition and rebound after hyperpolarization. A well-supported theory is that specific GABA interneuron subtypes hyperpolarize other GABA interneurons and inhibit their input on hippocampal excitatory signaling. This frees excitatory neurons from inhibition (“inhibition of inhibition”), leading to LTP.6 These findings implicate both a7 nAChRs on glutamatergic and GABAergic neurons as potential targets for improvement of memory and cognition decline in schizophrenia. The further involvement of GABAergic signaling and a7 nAChR activation is discussed below.

Alterations of Hippocampal Oscillations and LTP

Neurotransmission within the hippocampus is especially important for producing synchronized neural network oscillations that underlie cognition. EEGs demonstrate that people with schizophrenia have altered synchronized oscillatory activity when performing cognitive tasks, such as perceptualizing a construct from individual parts.12 One of the core cognitive deficits in schizophrenia involves working memory. Working memory dysfunction is believed to be partially caused by alternate patterns of hippocampal oscillatory activity, including gamma oscillatory activity, which is positively correlated with working memory.2 A7 nAChRs play a role in oscillation synchrony by alternating GABAergic signals, which in turn produce synchronization of oscillatory frequencies. Research in nonprimate animal models supports that functional loss of GABA-mediated inhibition weakens gamma oscillations and, in turn, memory-related cognition.6 These observations suggest a molecular and cellular basis for the development of novel therapeutic interventions for schizophrenia.

Gamma oscillations are not the only oscillation type believed to underlie schizophrenia's cognitive pathophysiology. Specific hippocampal theta and gamma wave coupling is also implicated in procognitive effects, including learning, memory, and consolidation of information.13 Theta oscillations coordinate sensorimotor information and integration by modulation of gamma waves. Stoiljkovic et al.13 demonstrated that a7 nAchRs modulate theta and gamma oscillations within the mouse hippocampus. In this study, a7 knockout mice and wild-type mice both demonstrated similar coupling of theta and gamma waves at baseline. However, stimulation of the a7 nAChR with administration of systemic a7 agonist increased theta-gamma coupling in wild-type mice but not in a7 knockout mice. This result indicates that the a7 receptor is necessary for theta-gamma oscillation synchronization. This enhanced theta-gamma coupling is necessary for effective potentiation of short-term and long-term memory. Research supports that drugs used in Alzheimer's disease modify hippocampal oscillations in a similar manner.6 Medications that alter hippocampal oscillation via a7 nAChRs have not yet been studied in people with schizophrenia, although disrupted coupling has been found in rat models of schizophrenia.13 Beyond specific receptor targets, patterns of oscillatory waves could provide a novel approach to pharmacological treatment of cognitive decline in schizophrenia.

Conclusion and Future Directions

Schizophrenia is a heterogeneous psychiatric disorder with many causes all classified as part of the “schizophrenia syndrome.” For instance, Chrna7 deletion (and thus loss of a7 nAChRs) is only one proposed mechanism contributing to cognitive pathophysiology in schizophrenia.9 In addition, hippocampal GABAergic and glutamatergic pathways can differ greatly with a7 nAChR density and functionality. Thus, the topic of this article may only represent one subtype of hundreds to millions of pathophysiologies involved in schizophrenia cognitive function. Furthermore, many other neural pathways, such as serotonergic and dopaminergic pathways in regions outside of the hippocampus, are implicated in cognitive functioning.2 Focusing only on the hippocampus simplifies the circuitry of cognition in schizophrenia.

Memory enhancement via hippocampal nAChRs on GABAergic interneurons and glutamatergic CA1 and CA3 neurons has been the focus of this article. Novel therapies aimed at weakening or strengthening the activity of these synapses via nAchRs have potential to alleviate cognitive abnormalities in patients with schizophrenia. However, pharmacological development is complicated by whether to target glutamatergic and/or GABAergic neurons, and of these neurons, which subtypes. Regions outside of the hippocampus with these subtypes may have the opposite role on cognition and cause unwanted side effects. Implications for future research include investigation of a7 nAChR stimulation in hippocampal GABA receptor knockout mice compared to NMDA and/or AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor knockout mice. Unfortunately, the genetics of knockout rodent models differ greatly from that of humans, but they do provide a foundation for research of cognition in schizophrenia. These proposed investigations and studies discussed here represent the crucial initial steps for understanding the pathophysiology of cognitive dysfunction and future treatments in schizophrenia.

References

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Authors

Candace Jones, BS, is a fourth-year Medical Student, University of Miami Miller School of Medicine.

Address correspondence to Candace Jones, BS, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, #1140, Miami, FL 33136; email: c.jones134@med.miami.edu.

Disclosure: The author has no relevant financial relationships to disclose.

The author thanks research mentors Claes Wahlestedt and Dr. Ingrid Barrera of the University of Miami and Dr. Brad Pearce of Emory University. The author also thanks her twin brother, whose courage and strength in coping with schizophrenia continues to inspire her every day.

10.3928/00485713-20180605-03

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