Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as ...neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.
Summary
Objective
Increased T2 relaxation time is often seen in temporal lobe epilepsy (TLE) with hippocampal sclerosis. Water content directly affects the effective T2 in a voxel. Our aim was to ...evaluate the relation between T2 values and two molecules associated with brain water homeostasis aquaporin 4 (AQP4) and chondroitin sulfate proteoglycan (CSPG), as well as cellular populations in the hippocampal region of patients with TLE.
Methods
Hippocampal T2 imaging and diffusion tensor imaging (DTI) were obtained from 42 drug‐resistant patients with TLE and 20 healthy volunteers (radiologic controls, RCs). A similar protocol (ex vivo) was applied to hippocampal sections from the same TLE cases and 14 autopsy control hippocampi (histologic and radiologic controls, HRCs), and each hippocampal subfield was evaluated. Hippocampal sections from TLE cases and HRC controls were submitted to immunohistochemistry for neurons (neuron nuclei NeuN), reactive astrocytes (glial fibrillary acidic protein GFAP), activated microglia (human leukocyte antigen‐D–related HLA‐DR), polarized AQP4, and CSPG.
Results
Patients with TLE had higher in vivo and ex vivo hippocampal T2 relaxation time. Hippocampi from epilepsy cases had lower neuron density, higher gliosis, decreased AQP4 polarization, and increased CSPG immunoreactive area. In vivo relaxation correlated with astrogliosis in the subiculum and extracellular CSPG in the hilus. Ex vivo T2 relaxation time correlated with astrogliosis in the hilus, CA4, and subiculum, and with microgliosis in CA1. The difference between in vivo and ex vivo relaxation ratio correlated with mean diffusivity and with the immunopositive area for CSPG in the hilus.
Significance
Our data indicate that astrogliosis, microgliosis, and CSPG expression correlate with the increased T2 relaxation time seen in the hippocampi of patients with TLE.
Abstract Temporal lobe epilepsy (TLE) and psychosis coexist more frequently than chance would predict. In this short review, clinical and neuropathological findings of schizophrenia, TLE, and ...psychosis of epilepsy are described to enhance our understanding of the noncoincidental association between these conditions. In addition, psychosis of epilepsy was included for the first time in the Diagnostic and Statistical Manual of Mental Disorders (DSM), in the recently launched 5th edition, and improvement in diagnostic criteria was highlighted. Since the hippocampus has long been considered an anatomical area involved in the pathophysiology of TLE and schizophrenia, neuropathological studies of psychoses of epilepsy may contribute to our understanding of the pathophysiology of psychosis in general. The discovery of shared mechanisms and/or affected neurochemicals in TLE and schizophrenia might disclose important clues on the vulnerability of patients with TLE to psychotic symptoms and be an opportunity for new treatment development. This article is part of a Special Issue entitled “NEWroscience 2013”.
Highlights • Cannabidiol into prefrontal cortex impaired fear memory consolidation only when it occurred at 5 h after conditioning. • Cannabidiol decreases dopamine release in prefrontal cortex ...following memory retrieval 5 days after training. • Post-training infusion of cannabidiol reduces genes expression in cortico-limbic circuits following memory retrieval.
ABSTRACTDespite the strong association between epilepsy and psychiatric comorbidities, data on clinicopathologic correlations are scant. We previously reported differential mossy fiber sprouting ...(MFS) in mesial temporal lobe epilepsy (MTLE) patients with psychosis (MTLE + P) and major depression (MTLE + D). Because neurotrophins (NTs) can promote MFS, here, we investigated MFS, neuronal density and immunoreactivity for the NT nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) in hippocampi of 14 MTLE patients without a psychiatric history, 13 MTLE + D, 13 MTLE + P, and 10 control necropsies. Mossy fiber sprouting correlated with granular layer NGF immunoreactivity and seizure frequency. Patients with secondarily generalized seizures exhibited less NGF immunoreactivity versus patients with complex partial seizures. There was greater NT immunoreactivity in MTLE versus control groups but lesser NT immunoreactivity in MTLE + P versus MTLE patients; these findings correlated with neuropsychologic scores. Patients with MTLE + D taking fluoxetine showed greater BDNF immunoreactivity than those not taking fluoxetine; MTLE + P patients taking haloperidol had decreased neuronal density and immunoreactivity for NGF and BDNF in specific subfields versus those not taking haloperidol. There were no differences in NT3 immunoreactivity among the groups. These findings support a close association between MFS and NT expression in the hippocampi of MTLE patients and suggest that distinct structural and neurochemical milieu may contribute to the genesis or maintenance of psychiatric comorbidities in MTLE.
Summary
Objective
Biologic substrates behind the close association between mesial temporal lobe epilepsy (MTLE) and psychiatric comorbidities are largely unknown. Heat shock protein 70 (HSP70) and ...HSP90 are ubiquitous molecular chaperones that play important roles in functions from cellular stress response to receptor trafficking control. There are controversial findings regarding HSP expression in epilepsy. Our goal was to examine HSP70 and HSP90 expression within the human hippocampal formation of MTLE patients with and without comorbid major depression and psychosis. In addition, we investigated the possible correlation between HSP expression and seizure outcome.
Methods
MTLE hippocampi of subjects without psychiatric history, MTLE and major depression, and MTLE and interictal psychosis derived from epilepsy surgery and control necropsies were investigated for neuronal densities, HSP70 and HSP90 immunoreactive area.
Results
Increased HSP expression in MTLE and decreased HSP expression in MTLE with psychosis cases were detailed. Patients taking fluoxetine showed increased HSP90 expression in CA1, and those taking haloperidol decreased HSP90 in the granular layer and subiculum. MTLE patients with complete seizure remission presented with decreased HSP70 expression in CA4 and subiculum and decreased HSP90 expression in the granular layer.
Significance
The present results provide the first demonstration of HSP expression in human MTLE hippocampal formation with and without psychiatric comorbidities. Distinct HSP70 and HSP90 expression might explain some of the structural and synaptic alterations differentially regulated in MTLE with and without psychiatric comorbidities. Increased HSPs expression in key hippocampal subfields would reflect increased epileptogenicity and poorer outcome of epilepsy surgery.
Summary
Objective
Hippocampal sclerosis is a common finding in patients with temporal lobe epilepsy (TLE), and magnetic resonance imaging (MRI) studies associate the reduction of hippocampal volume ...with the neuron loss seen on histologic evaluation. Astrogliosis and increased levels of chondroitin sulfate, a major component of brain extracellular matrix, are also seen in hippocampal sclerosis. Our aim was to evaluate the association between hippocampal volume and chondroitin sulfate, as well as neuronal and astroglial populations in the hippocampus of patients with TLE.
Methods
Patients with drug‐resistant TLE were subdivided, according to hippocampal volume measured by MRI, into two groups: hippocampal atrophy (HA) or normal volume (NV) cases. Hippocampi from TLE patients and age‐matched controls were submitted to immunohistochemistry to evaluate neuronal population, astroglial population, and chondroitin sulfate expression with antibodies against neuron nuclei protein (NeuN), glial fibrillary acidic protein (GFAP), and chondroitin sulfate (CS‐56) antigens, respectively.
Results
Both TLE groups were clinically similar. NV cases had higher hippocampal volume, both ipsilateral and contralateral, when compared to HA. Compared to controls, NV and HA patients had reduced neuron density, and increased GFAP and CS‐56 immunopositive area. There was no statistical difference between NV and HA groups in neuron density or immunopositive areas for GFAP and CS‐56. Hippocampal volume correlated positively with neuron density in CA1 and prosubiculum, and with immunopositive areas for CS‐56 in CA1, and negatively with immunopositive area for GFAP in CA1. Multiple linear regression analysis indicated that both neuron density and CS‐56 immunopositive area in CA1 were statistically significant predictors of hippocampal volume.
Significance
Our findings indicate that neuron density and chondroitin sulfate immunopositive area in the CA1 subfield are crucial for the hippocampal volume, and that chondroitin sulfate is important for the maintenance of a normal hippocampal volume in some cases with severe neuron loss.
The present study reports the behavioral, electrophysiological, and neuropathological effects of cannabidiol (CBD), a major non-psychotropic constituent of
, in the intrahippocampal ...pilocarpine-induced status epilepticus (SE) rat model. CBD was administered before pilocarpine-induced SE (group SE+CBDp) or before and after SE (group SE+CBDt), and compared to rats submitted only to SE (SE group), CBD, or vehicle (VH group). Groups were evaluated during SE (behavioral and electrophysiological analysis), as well as at days one and three post-SE (exploratory activity, electrophysiological analysis, neuron density, and neuron degeneration). Compared to SE group, SE+CBD groups (SE+CBDp and SE+CBDt) had increased SE latency, diminished SE severity, increased contralateral afterdischarge latency and decreased relative powers in delta (0.5-4 Hz) and theta (4-10 Hz) bands. Only SE+CBDp had increased vertical exploratory activity 1-day post SE and decreased contralateral relative power in delta 3 days after SE, when compared to SE group. SE+CBD groups also showed decreased neurodegeneration in the hilus and CA3, and higher neuron density in granule cell layer, hilus, CA3, and CA1, when compared to SE group. Our findings demonstrate anticonvulsant and neuroprotective effects of CBD preventive treatment in the intrahippocampal pilocarpine epilepsy model, either as single or multiple administrations, reinforcing the potential role of CBD in the treatment of epileptic disorders.
PDF
