Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

Background

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission.

Objective

Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined.

Methods

Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone β-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD).

Results

Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet.

Conclusions

Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.

Aims

Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown.

Methods

Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression.

Results

Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases.

Conclusions

In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible antiseizure treatment for RE may involve the use of gap junction blockers.

Medium-sized spiny neurons (MSNs), the predominant neuronal population of the striatum, are an integral component of the many cortical and limbic pathways associated with reward-related behaviors. A differential role of the D1 receptor-enriched (D1) MSNs of the striatonigral direct pathway, as compared with the D2 receptor-enriched (D2) MSNs of the striatopallidal indirect pathway, in mediating the addictive behaviors associated with cocaine is beginning to emerge. However, whether opioids, well-known analgesics with euphoric properties, similarly induce dissociable signaling adaptations in these neurons remains unclear. Transgenic mice expressing green fluorescent protein (GFP)-labeled D1 or D2 neurons were implanted with intravenous jugular catheters. Mice learned to self-administer 0.1mg/kg/infusion of the opioid remifentanil during 2h sessions over 13 contiguous days. Thereafter, the electrophysiological properties of D1- and D2-MSNs in the shell region of the nucleus accumbens (NAc) were assessed. We found that prior opioid exposure did not alter the basic membrane properties nor the kinetics or amplitude of miniature excitatory postsynaptic currents (mEPSCs). However, when challenged with the mu opioid receptor (μOR) agonist DAMGO, the characteristic inhibitory profile of this receptor was altered. DAMGO inhibited the frequency of mEPSCs in D1-MSNs from control mice receiving saline and in D2-MSNs from mice exposed to remifentanil or saline, but this inhibitory profile was reduced in D1-MSNs from mice receiving remifentanil. Remifentanil exposure also altered the probability of glutamate release onto D1-, but not D2-MSNs. Together these results suggest a D1-pathway specific effect associated with the acquisition of opioid-seeking behaviors.

Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain.

Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.