Capturing schizophrenia-like prodromal symptoms in a spinocerebellar ataxia-17 transgenic rat.

RATIONALE: The polyglutamine disease spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease leading to severe neurological symptoms during development. Additionally, patients affected by SCA17 display psychosis earlier than their motor disorders. OBJECTIVE: Here the putative psychotic phenotype and endophenotype of transgenic SCA17 rats was examined. METHODS: The expression of schizophrenia-like symptoms was evaluated over a longitudinal period before and after the onset of neurological symptoms in SCA17. To this end, transgenic SCA17 rats' monoamine neurotransmission was investigated along with their locomotion at baseline and in response to amphetamine using in-vivo microdialysis in free moving conditions, their sensorimotor gating using pre-pulse inhibition of startle reaction, and their object memory using the novel object recognition test as an index of cognitive impairments. RESULTS: Presymptomatic SCA17 rats displayed dysregulated monoamine levels at baseline and in response to amphetamine compared with control wild-type (wt) rats. At that stage, neither amphetamine-induced hyperlocomotion nor sensorimotor gating differed from that in wt rats. Symptomatic SCA17 rats developed sensorimotor gating deficits and also showed an impaired object memory, while their monoaminergic responses remained supersensitive to amphetamine. CONCLUSIONS: The data of the present study demonstrate a neurochemical endophenotype in SCA17 rats resembling that of prodromal schizophrenia. These findings suggest that a sensitization of the monoamine systems arises early in adulthood in SCA17 rats and may predispose them to express schizophrenia-like symptoms later in life.

Methods of automated absence seizure detection, interference by stimulation, and possibilities for prediction in genetic absence models.

BACKGROUND: Genetic rat models for childhood absence epilepsy have become instrumental in developing theories on the origin of absence epilepsy, the evaluation of new and experimental treatments, as well as in developing new methods for automatic seizure detection, prediction, and/or interference of seizures. METHOD: Various methods for automated off and on-line analyses of ECoG in rodent models are reviewed, as well as data on how to interfere with the spike-wave discharges by different types of invasive and non-invasive electrical, magnetic, and optical brain stimulation. Also a new method for seizure prediction is proposed. RESULTS: Many selective and specific methods for off- and on-line spike-wave discharge detection seem excellent, with possibilities to overcome the issue of individual differences. Moreover, electrical deep brain stimulation is rather effective in interrupting ongoing spike-wave discharges with low stimulation intensity. A network based method is proposed for absence seizures prediction with a high sensitivity but a low selectivity. Solutions that prevent false alarms, integrated in a closed loop brain stimulation system open the ways for experimental seizure control. CONCLUSIONS: The presence of preictal cursor activity detected with state of the art time frequency and network analyses shows that spike-wave discharges are not caused by sudden and abrupt transitions but that there are detectable dynamic events. Their changes in time-space-frequency characteristics might yield new options for seizure prediction and seizure control.

The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies.

First characterized in 1982, the genetic absence epilepsy rat from Strasbourg (GAERS) has emerged as an animal model highly reminiscent of a specific form of idiopathic generalized epilepsy. Both its electrophysiological (spike-and-wave discharges) and behavioral (behavioral arrest) features fit well with those observed in human patients with typical absence epilepsy and required by clinicians for diagnostic purposes. In addition, its sensitivity to antiepileptic drugs closely matches what has been described in the clinic, making this model one of the most predictive. Here, we report how the GAERS, thanks to its spontaneous, highly recurrent and easily recognizable seizures on electroencephalographic recordings, allows to address several key-questions about the pathophysiology and genetics of absence epilepsy. In particular, it offers the unique possibility to explore simultaneously the neural circuits involved in the generation of seizures at different levels of integration, using multiscale methodologies, from intracellular recording to functional magnetic resonance imaging. In addition, it has recently allowed to perform proofs of concept for innovative therapeutic strategies such as responsive deep brain stimulation or synchrotron-generated irradiation based radiosurgery.

Lessons learned from the transgenic Huntington's disease rats.

Huntington's disease (HD) is a fatal inherited disorder leading to selective neurodegeneration and neuropsychiatric symptoms. Currently, there is no treatment to slow down or to stop the disease. There is also no therapy to effectively reduce the symptoms. In the investigation of novel therapies, different animal models of Huntington's disease, varying from insects to nonhuman primates, have been created and used. Few years ago, the first transgenic rat model of HD, carrying a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter, was introduced. We have been using this animal model in our research and review here our experience with the behavioural, neurophysiological, and histopathological phenotype of the transgenic Huntington's disease rats with relevant literature.

Neurobehavioral tests in rat models of degenerative brain diseases.

Each translational approach in medical research forces the establishment of neurobehavioral screening systems, dedicated to fill the gap between postgenomic generation of state-of-the-art animal models (i.e. transgenic rats) on the one hand and their added value for really predictive experimental preclinical therapy on the other. Owing to these developments in the field, neuroscientists are frequently challenged by the task of detecting discrete behavioral differences in rats. Systematic, comprehensive phenotyping covers these needs and represents a central part of the process. In this chapter, we provide an overview on theoretical issues related to comprehensive neurobehavioral phenotyping of rats and propose specific classical procedures, protocols (similar to the SHIRPA approach in mice), as well as techniques for repeated, intraindividual phenotyping. Neurological testing of rats, motorfunctional screening using the accelerod approach, emotional screening using the social interaction test of anxiety, and testing of sensorimotoric gating functions by prepulse inhibition of the startle response are provided in more detail. This description is completed by an outlook on most recent developments in the field dealing with automated, intra-home-cage technologies, allowing continuous screening in rats in various behavioral and physiological dimensions on an ethological basis.

Impaired cavernous reinnervation after penile nerve injury in rats with features of the metabolic syndrome.

INTRODUCTION: The metabolic syndrome is a cluster of cardiovascular risk factors that predispose toward the development of diseases such as diabetes. Erectile dysfunction (ED) is common in men with metabolic syndrome, but its etiology is poorly understood. Pro-erectile nitrergic nerves innervating penile erectile tissue are also susceptible to mechanical injury during pelvic surgical procedures, which can lead to sexual dysfunction. AIMS: The aims of this article are: (i) to examine erectile function in an experimental model of metabolic syndrome, the phosphoenolpyruvate carboxykinase (PEPCK)-overexpressing rat; and (ii) to study function and cavernous reinnervation after penile nerve crush injury, which permits regeneration, in transgenic rats. METHODS: We analyzed the density of noradrenergic and nitrergic nerves and performed organ bath pharmacology to assess neurogenic activity. MAIN OUTCOME MEASURES: By analyzing changes in neural structure, function, and pharmacologic responses of cavernous tissue after nerve crush injury, we were able to reveal neurologic deficits in rats with metabolic syndrome. RESULTS: Animals with features of metabolic syndrome did not develop notable changes in cavernous autonomic nerve density or nerve-evoked smooth muscle activity. However, regeneration of nitrergic nerves after crush injury in transgenic rats was impaired compared with injured controls. This was manifested as a deficit in axon regrowth and responses to axon activation. However, unlike injured controls, injured PEPCK-overexpressing rats did not develop a reduced maximal response to the nitric oxide (NO) donor, sodium nitroprusside. This suggests preserved NO responsiveness in tissues from rats with metabolic syndrome, despite impaired regeneration and return of function. CONCLUSIONS: This study revealed that rats with features of metabolic syndrome display impaired cavernous nerve regeneration after penile nerve injury, but the degree of functional impairment may be attenuated due to reduced plasticity of NO signaling. This reinnervation deficit may be of clinical relevance for understanding why ED persists in some (particularly aged) men after pelvic surgery.

Delivery of sry1, but not sry2, to the kidney increases blood pressure and sns indices in normotensive wky rats.

BACKGROUND: Our laboratory has shown that a locus on the SHR Y chromosome increases blood pressure (BP) in the SHR rat and in WKY rats with the SHR Y chromosome (SHR/y rat). A candidate for this Y chromosome hypertension locus is Sry, a gene that encodes a transcription factor responsible for testes determination. The SHR Y chromosome has six divergent Sry loci. The following study examined if exogenous Sry1 or Sry2 delivered to the kidney would elevate renal tyrosine hydroxylase, renal catecholamines, plasma catecholamines and telemetered BP over a 28 day period. We delivered 50 mug of either the expression construct Sry1/pcDNA 3.1, Sry2/pcDNA 3.1, or control vector into the medulla of the left kidney of normotensive WKY rats by electroporation. Weekly air stress was performed to determine BP responsiveness. Separate groups of animals were tested for renal function and plasma hormone patterns and pharmacological intervention using alpha adrenergic receptor blockade. Pre-surgery baseline and weekly blood samples were taken from Sry1 electroporated and control vector males for plasma renin, aldosterone, and corticosterone. BP was measured by telemetry and tyrosine hydroxylase and catecholamines by HPLC with electrochemical detection. RESULTS: In the animals receiving the Sry1 plasmid there were significant increases after 21 days in resting plasma norepinephrine (NE, 27%) and renal tyrosine hydroxylase content (41%, p < .05) compared to controls. BP was higher in animals electroporated with Sry1 (143 mmHg, p < .05) compared to controls (125 mmHg) between 2-4 weeks. Also the pressor response to air stress was significantly elevated in males electroporated with Sry1 (41 mmHg) compared to controls (28 mmHg, p < .001). Sry2 did not elevate BP or SNS indices and further tests were not done. The hormone profiles for plasma renin, aldosterone, and corticosterone between electroporated Sry1 and control vector males showed no significant differences over the 28 day period. Alpha adrenergic receptor blockade prevented the air stress pressor response in both strains. Urinary dopamine significantly increased after 7 days post Sry electroporation. CONCLUSION: These results are consistent with a role for Sry1 in increasing BP by directly or indirectly activating renal sympathetic nervous system activity.