Galanin contributes to monoaminergic dysfunction and to dependent neurobehavioral comorbidities of epilepsy

Abstract

Status epilepticus (SE) in rats, along with chronic epilepsy, leads to the development of behavioral impairments resembling depressive disorder and/or attention deficit/hyperactivity disorder (ADHD), thus reflecting respective comorbidities in epilepsy patients. Suppressed neurotransmitter tone in the raphe nucleus (RN)-prefrontal cortex (PFC) serotonergic pathway and in the locus coeruleus (LC)-PFC noradrenergic pathway underlies depressive- and impulsive- like behavioral deficits respectively. We examined possible mechanisms leading to the monoamine dysfunction in brainstem efferents, namely modulatory effects of the neuropeptide galanin on serotonin (5-HT) and norepinephrine (NE) signaling. SE was induced in young adult male Wistar rats by LiCl and pilocarpine. Epileptic rats were categorized vis-à-vis behavioral deficits as not impaired, “depressed” and “impulsive”. Depressive- and impulsive- like behaviors were examined in the forced swimming test (FST). The strength of serotonergic transmission in RN-PFC and of noradrenergic transmission in LC-PFC was analyzed using in vivo fast scan cyclic voltammetry. Galanin receptor type 1 (GalR1) / type 2 (GalR2) antagonist M40, and a preferential GalR2 antagonist M871 were administered over 3 days locally into either RN or LC by means of ALZET osmotic minipumps connected to locally implanted infusion cannulas. Intra-RN injection of M40 improved serotonergic tone and depressive-like behavior in epileptic “depressed” rats. Intra-LC injection of M40 improved noradrenergic tone and impulsive-like behavior in epileptic “impulsive” rats. The effects of M40 were only observed in impaired subjects. The treatment did not modify neurotransmission and behavior in naïve and epileptic not impaired rats; in “depressed” rats the effects were limited to serotonergic transmission and immobility, while in “impulsive” rats – to noradrenergic transmission and struggling behavior. Intra-RN administration of M871 exacerbated depressive-like behavior, but had no effects on any other of the examined parameters in any category of animals. These findings suggest that endogenous galanin, acting through GalR1 may be involved in the pathophysiology of epilepsy-associated depression and ADHD via inhibiting RN-PFC serotonergic and LC-PFC noradrenergic transmissions respectively.

The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy

“…We studied the distribution of galanin, a bioactive peptide shown to modulate brainstem serotonergic and noradrenergic systems in experimental models ( Medel-Matus et al , 2017 ) and observed reduced labelling in the SUDEP groups. Galanergic neurons in the rodent medulla are concentrated in the nucleus of the solitary tract, VLM, retrotrapezoid nucleus ( Bochorishvili et al , 2012 ; Spirovski et al , 2012 ) and locus coeruleus ( Spirovski et al , 2012 ).…”

“…The retrotrapezoid nucleus in animals, critical for central respiratory chemoreception, has glutamatergic and galanergic neurons that synapse with NK1R + neurons of the pre-BötC and are considered to activate breathing ( Bochorishvili et al , 2012 ); local galanin-expressing NK1R + neurons in the VLM are also activated following hypoxia and hypercapnia ( Spirovski et al , 2012 ). Other experimental studies have reported that micro-injection of galanin into the pre-BötC exerts a central respiratory depression ( Abbott et al , 2009 ) and galanin also mediates inhibition of serotonergic transmission in the medullary raphe ( Medel-Matus et al , 2017 ). Interestingly, rodent anatomical studies indicate differential sources of galanergic input to specific medullary regions; for example, there is no projection from the retrotrapezoid galanergic neurons to the medullary raphe ( Bochorishvili et al , 2012 ).…”

What are the challenges with the pharmacological management of epilepsy in patients with Attention Deficit Hyperactivity Disorder (ADHD)?

“…The co-occurrence of ADHD and epilepsy may be based on several mechanisms, as underlying brain abnormalities, a genetic predisposition, a dysregulation of the neurotransmitters system [5], the chronic effects of ongoing seizures, the side effects of AEDs, and the presence of psychosocial factors [6].…”

Home-cage Monitoring Ascertains Signatures of Ictal and Interictal Behavior In Mouse Models of Generalized Seizures

“…Aside from measurements of learning and memory, assessments of interictal emotional behavior in rodents have relied heavily on phenotyping batteries (23)(24)(25) to identify features of "depression-related" or "anxiety-related" behavior extrapolated from assessments of behavioral despair (e.g., forced swim test) or exploration (e.g., open field / elevated plus maze tests). While these tests are certainly convenient and offer a reasonably high throughput, they are short in duration (5-10 minutes long) and are often measured during the biological night (when lights are on).…”