Pathological Correlates of Cognitive Decline in Parkinson's Disease: From Molecules to Neural Networks.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra and appearance of protein aggregates (Lewy bodies) consisting predominantly of α-synuclein in neurons. PD is currently recognized as a multisystem disorder characterized by severe motor impairments and various non-motor symptoms. Cognitive decline is one of the most common and worrisome non-motor symptoms. Moderate cognitive impairments (CI) are diagnosed already at the early stages of PD, usually transform into dementia. The main types of CI in PD include executive dysfunction, attention and memory decline, visuospatial impairments, and verbal deficits. According to the published data, the following mechanisms play an essential role demonstrates a crucial importance in the decline of the motor and cognitive functions in PD: (1) changes in the conformational structure of transsynaptic proteins and protein aggregation in presynapses; (2) synaptic transmission impairment; (3) neuroinflammation (pathological activation of the neuroglia); (4) mitochondrial dysfunction and oxidative stress; (5) metabolic disorders (hypometabolism of glucose, dysfunction of glycolipid metabolism; and (6) functional rearrangement of neuronal networks. These changes can lead to the death of dopaminergic cells in the substantia nigra and affect the functioning of other neurotransmitter systems, thus disturbing neuronal networks involved in the transmission of information related to the regulation of motor activity and cognitive functions. Identification of factors causing detrimental changes in PD and methods for their elimination will help in the development of new approaches to the therapy of PD. The goal of this review was to analyze pathological processes that take place in the brain and underlie the onset of cognitive disorders in PD, as well as to describe the impairments of cognitive functions in this disease.

Uridine as a Regulator of Functional and Ultrastructural Changes in the Brain of Rats in a Model of 6-OHDA-Induced Parkinson's Disease.

Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca2+ retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed.

Phase relations of theta oscillations in a computer model of the hippocampal CA1 field: Key role of Schaffer collaterals.

The hippocampal theta rhythm (4-12 Hz) is one of the most important electrophysiological processes in the hippocampus, it participates in cognitive hippocampal functions, such as navigation in space, novelty detection, and declarative memory. We use neural network modeling to study the mechanism of theta rhythm emergence in the CA1 microcircuitry. Our model of the CA1 field includes biophysical representation of major cell types related to the theta rhythm emergence: excitatory pyramidal cells and two types of inhibitory interneurons, PV+ basket cells and oriens lacunosum-moleculare (OLM) cells. The main inputs to the CA1 cells come from the entorhinal cortex via perforant pathway, the CA3 field via Schaffer collaterals, and the medial septum via fimbria-fornix. By computer simulations we investigated the influence of each input, intrinsic parameters of neurons, and connections between neurons on phase coupling between the theta rhythm and the firing of pyramidal, PV+ basket and OLM cells in the CA1. We found that the input from the CA3 field via Schaffercollaterals plays a major role in the formation of phase relations that have been observed in experiments in vivo. The direct input from the medial septum participates in the formation of proper phase relations, but it is not crucial for the production of the theta rhythm in CA1 neural populations.

Alterations of Coherent Theta and Gamma Network Oscillations as an Early Biomarker of Temporal Lobe Epilepsy and Alzheimer's Disease.

Alzheimer's disease (AD) and temporal lobe epilepsy (TLE) are the most common forms of neurodegenerative disorders characterized by the loss of cells and progressive irreversible alteration of cognitive functions, such as attention and memory. AD may be an important cause of epilepsy in the elderly. Early diagnosis of diseases is very important for their successful treatment. Many efforts have been done for defining new biomarkers of these diseases. Significant advances have been made in the searching of some AD and TLE reliable biomarkers, including cerebrospinal fluid and plasma measurements and glucose positron emission tomography. However, there is a great need for the biomarkers that would reflect changes of brain activity within few milliseconds to obtain information about cognitive disturbances. Successful early detection of AD and TLE requires specific biomarkers capable of distinguishing individuals with the progressing disease from ones with other pathologies that affect cognition. In this article, we review recent evidence suggesting that magnetoencephalographic recordings and coherent analysis coupled with behavioral evaluation can be a promising approach to an early detection of AD and TLE. Highlights -Data reviewed include the results of clinical and experimental studies.-Theta and gamma rhythms are disturbed in epilepsy and AD.-Common and different behavioral and oscillatory features of pathologies are compared.-Coherent analysis can be useful for an early diagnostics of diseases.

Fatty acid amide hydrolase inhibitor URB597 may protect against kainic acid-induced damage to hippocampal neurons: Dependence on the degree of injury.

OBJECTIVE: Status epilepticus (SE) provokes changes, which lead to neuronal alterations. Endocannabinoids (eCBs) can affect the neuronal survival during excitotoxicity and brain damage. Using a kainic acid (KA)-induced experimental SE model, we investigated whether cellular changes entail damage to endoplasmic reticulum (ER), mitochondria, and nuclei in hippocampal cells (CA1 field), and whether these alterations can be diminished by treatment with URB597, an inhibitor of eCB enzymatic degradation. MATERIAL AND METHODS: SE was induced in Wistar rats by the microinjection of KA into the lateral ventricle. URB597 or a vehicle (10% DMSO) were injected in the same way into the brain of animals 24h after the KA infusion and then daily for the next nine days. The behavior of animals was controlled visually and recorded with a video system. The intensity of SE significantly varied in different animals. Convulsive (stages 3-5 according to the Racine scale) and nonconvulsive seizures (mainly stages 1, 2 and rarely 3, 4) were recognized. RESULTS: Two weeks after SE, a significant loss of hippocampal cells occurred in animals with KA injections. In survived cells, ultrastructural alterations in ER, mitochondria, and nuclei of hippocampal neurons were observed. The degree of cell injury depended on the severity of SE. Alterations evoked by moderate seizures were prevented or diminished by URB597, but strong seizures induced mostly irreversible damage. CONCLUSIONS: The beneficial impact of the FAAH inhibitor URB597 can give impetus to the development of novel neuroprotective strategies.

Modeling synchronous theta activity in the medial septum: key role of local communications between different cell populations.

It is widely believed that the theta rhythm in the hippocampus is caused by the rhythmic input from the medial septum-diagonal band of Broca (MSDB). The main MSDB output is formed by GABAergic projection neurons which are divided into two subpopulations and fire at different phases of the hippocampal theta rhythm. The MSDB also contains projection cholinergic, glutamatergic, and non-projection GABAergic neurons. These cell populations innervate each other and also GABAergic projection neurons and participate in the formation of the synchronous rhythmic output to the hippocampus. The purpose of this study is to work out a model of interactions between all neural populations of the MSDB that underlie the formation of the synchronous septal theta signal. The model is built from biologically plausible neurons of the Hodgkin-Huxley type and its architecture reflects modern data on the morphology of neural connections in the MSDB. The model satisfies the following requirements: (1) a large portion of neurons is fast-spiking; (2) the subpopulations of GABAergic projection neurons contain endogenous pacemaker neurons; (3) the phase shift of activity between subpopulations of GABAergic projection neurons is equal to about 150°; and (4) the strengths of bidirectional connections between the subpopulations of GABAergic projection cells are different. It is shown that the theta rhythm generation can be performed by a system of glutamatergic and GABAergic non-projection neurons. We also show that bursting pacemaker neurons in the subpopulation of projection GABAergic neurons play a significant role in the formation of stable antiphase outputs from the MSDB to the hippocampus.

Theta oscillations and reactivity of hippocampal stratum oriens neurons.

The supposition was advanced that the neuronal theta rhythmicity is the key mode of signal selection at the hippocampal level. To address this hypothesis, the experimental data on the responses of putative hippocampal interneurons of the stratum oriens CA1-CA3 to stimulation during enhanced theta rhythm and after its blockade are reviewed. Both a strong increase and a decrease of the natural theta rhythm disturbed the reactions of hippocampal neurons; during theta augmentation, the responses were masked or disappeared, and after theta blockade, they lost the ability to habituate. In both cases, two important events were broken: the resetting of the background activity and the phase-locking of theta cycles to stimulus. These data allow one to suppose that only important stimuli are normally capable to evoke these events and these stimuli are selected for recording. When the response to a significant stimulus occurs, the following theta prevents the responses to other stimuli. This probably protects the hippocampal activity from interference from irrelevant signals. Presumably, the absence of the theta deprives the hippocampus of this protection. During enhanced and persistent theta oscillations, the reset disappeared and theta bursts were generated without stimulus locking. In this state, the system is probably closed and the information cannot be recorded. During the theta blockade, the reset was too long and did not habituate. In this case, the system is open for any signals and the hippocampus loses the ability to select signal. This analysis suggests that information selection in the hippocampus may be performed with the participation of nonpyramidal neurons.

Theta activity of septal neurons during different epileptic phases: the same frequency but different significance?

The multiunit activity in the medial septal-diagonal band complex (MSDB) and field potentials of the hippocampus were simultaneously recorded in waking healthy rabbits (control) and in the same animals that were then exposed to kindling stimulation of the perforant path. In the control, the bursts of spikes in one group of rhythmic MSDB neurons phase-locked to the top of theta waves in the hippocampus, and in the second group, to the trough of these waves. The stimulation evoked seizure afterdischarges in the hippocampus and seizure bursts of spikes separated by periods of inhibition in MSDB neurons. In the first group of septal cells, seizure bursts coincided with inhibitory periods between afterdischarges in the hippocampus; in the second group, these bursts were observed during seizure afterdischarges, suggesting that different MSDB cells play opposite roles in the development of seizures. Evoked afterdischarges were spontaneously followed by recurrent ictal events; neuronal oscillations at the theta (6-7 Hz) or "twice-theta" frequency (12-14 Hz) preceded these secondary epileptic discharges. As a result of kindling, interictal spikes were recorded in the hippocampus; at the same time, synchronous bursts of many cells appeared in the MSDB. In the epileptic brain, the frequency of both the hippocampal theta rhythm and MSDB neuronal theta bursts increased; in the septum, an augmentation of neuronal rhythmicity was also observed. Theta oscillations, either spontaneous or evoked by sensory stimulation, abolished the epileptiform events. Evidently, the activities within the theta range during preictal and interictal periods are of different significance in the generation of seizures.

Disturbance of the correlation between hippocampal and septal EEGs during epileptogenesis.

Field potentials of the hippocampus and the medial septal-diagonal band complex (MSDB) were recorded in the control and during the kindling stimulation of the perforant path in waking guinea pigs. Changes in the correlation of activities of these structures during stimulation-evoked seizures (model of acute epilepsy) and during epileptogenesis elicited by the kindling (model of chronic epilepsy) were analysed. In the control, a high correlation between the background activities of the hippocampus and MSDB was observed. In the first days of stimulation at the parameters that evoked seizure discharges in the hippocampus, the MSDB did not show the epileptiform activity; however, repeated daily stimulation gave rise to epileptiform discharges, which increased with time. As a result of kindling, the MSDB became capable of generating seizure activity irrespective of the hippocampus. The degree of correlation between the activities of the two structures sharply decreased during "acute" and "chronic" seizures. In the process of kindling, a progressive disintegration of activities of the hippocampus and MSDB was revealed, indicating the disturbance of the functioning of septohippocampal network during epileptogenesis. The data obtained add to the knowledge about the mechanisms of temporal lobe epilepsy and may help to develop new approaches to the therapy of this disease.

Repeated blockade of GABAA receptors in the medial septal region induces epileptiform activity in the hippocampus.

Changes in the activity of putative interneurons of the stratum oriens of the hippocampus and hippocampal EEG after the delivery of the GABAA receptor antagonist bicuculline (1.0nmol/1microl) to the medial septal region were investigated in awake rabbits. The injection of bicuculline produced a sharp increase in the firing rate in 94.3% of hippocampal cells. The effect of bicuculline on the neuronal theta rhythmicity depended on the number of injections. The first five daily infusions decreased the theta activity in 85.7% of cells. On the fourth to fifth experimental days paroxysmal discharges and 8-15Hz oscillations were recorded in the hippocampal EEG. Six to seven further daily bicuculline injections following a brief diminution of theta activity produced a sharp augmentation of theta oscillations in 78.9% of cells and provoked seizures. Immediately before seizures, stabilization of theta bursts and an increase in burst frequency was usually observed in putative interneurons. During seizures, neuronal rhythmic activity was either disordered and then turned into seizure discharges or was inhibited, partially or completely. In the hippocampal EEG, the power of theta rhythm before seizures usually strongly increased compared with controls. Injection of the GABAA agonist muscimol (30nmol/1microl) 15min before bicuculline infusion prevented the development of seizures. These findings suggest that the interplay between septal neurons via GABAA receptors is critical in the tuning of septal output signals that insure generation of natural theta rhythm as well as adequate functioning of the hippocampus.