Molecular Specialization of GABAergic Synapses on the Soma and Axon in Cortical and Hippocampal Circuit Function and Dysfunction

The diversity of inhibitory interneurons allows for the coordination and modulation of excitatory principal cell firing. Interneurons that release GABA (γ-aminobutyric acid) onto the soma and axon exert powerful control by virtue of proximity to the site of action potential generation at the axon initial segment (AIS). Here, we review and examine the cellular and molecular regulation of soma and axon targeting GABAergic synapses in the cortex and hippocampus. We also describe their role in controlling network activity in normal and pathological states. Recent studies have demonstrated a specific role for postsynaptic dystroglycan in the formation and maintenance of cholecystokinin positive basket cell terminals contacting the soma, and postsynaptic collybistin in parvalbumin positive chandelier cell contacts onto the AIS. Unique presynaptic molecular contributors, LGI2 and FGF13, expressed in parvalbumin positive basket cells and chandelier cells, respectively, have also recently been identified. Mutations in the genes encoding proteins critical for somatic and AIS inhibitory synapses have been associated with human disorders of the nervous system. Dystroglycan dysfunction in some congenital muscular dystrophies is associated with developmental brain malformations, intellectual disability, and rare epilepsy. Collybistin dysfunction has been linked to hyperekplexia, epilepsy, intellectual disability, and developmental disorders. Both LGI2 and FGF13 mutations are implicated in syndromes with epilepsy as a component. Advancing our understanding of the powerful roles of somatic and axonic GABAergic contacts in controlling activity patterns in the cortex and hippocampus will provide insight into the pathogenesis of epilepsy and other nervous system disorders

Behavioral Arrest and a Characteristic Slow Waveform Are Hallmark Responses to Selective 5-HT2A Receptor Activation

© 2021, The Author(s). Perception, emotion, and mood are powerfully modulated by serotonin receptor (5-HTR) agonists including hallucinogens. The 5-HT2AR subtype has been shown to be central to hallucinogen action, yet the precise mechanisms mediating the response to 5-HT2AR activation remain unclear. Hallucinogens induce the head twitch response (HTR) in rodents, which is the most commonly used behavioral readout of hallucinogen pharmacology. While the HTR provides a key behavioral signature, less is known about the meso level changes that are induced by 5-HT2AR activation. In response to administration of the potent and highly selective 5-HT2AR agonist 25I-NBOH in mice, we observe a disorganization of behavior which includes frequent episodes of behavioral arrest that consistently precede the HTR by a precise interval. By combining behavioral analysis with electroencephalogram (EEG) recordings we describe a characteristic pattern composed of two distinctive EEG waveforms, Phase 1 and Phase 2, that map onto behavioral arrest and the HTR respectively, with the same temporal separation. Phase 1, which underlies behavioral arrest, is a 3.5–4.5 Hz waveform, while Phase 2 is slower at 2.5–3.2 Hz. Nicotine pretreatment, considered an integral component of ritualistic hallucinogen practices, attenuates 25I-NBOH induced HTR and Phase 2 waveforms, yet increases behavioral arrest and Phase 1 waveforms. Our results suggest that in addition to the HTR, behavioral arrest and characteristic meso level slow waveforms are key hallmarks of the response to 5-HT2AR activation. Increased understanding of the response to serotonergic hallucinogens may provide mechanistic insights into perception and hallucinations, as well as regulation of mood

The role of cues and the hippocampus in home base behaviour

xv, 232 leaves : ill. ; 29 cm.The thesis examines the ability of animals to construct a home base. The home base is a point in space where animals rear, groom, and circle and is a primary element in organized spatial behaviour (Eilam and Golani 1989). Once animals establish a home base, they make outward trips and stops, and after a series of trips and stops they return again to the home base. The home base behaviour of animals acts as a platform for asking questions about the cognitive organization of an environment. The thesis describes five main findings. Control and hippocampectomized animals use (1) proximal and (2) distal cues to form a home base and organize their behaviour. (3) Control and olfactory bulbectomized animals form home bases in the dark where as hippocampectomized animals are impaired suggesting self-movement but not olfactory cues play a role in home base behaviour. A final set of experiments demonstrated that control and hippocampectomized animals learn the position of (4) proximal and (5) distal cues so that in the cue's absence, animals still form a home base at that position. The demonstration that a central feature of exploratory behaviour, establishing a home base, is preserved in hippocampectomized rats in relation to proximal, distal, and conditioned visual cues - reveals that exploratory behaviour remains organized after hippocampal lesions. The inability of hippocampectomized rats to form a virtual home base in the absence of visual cues is discussed in relation to the idea that the hippocampus contributes to inertial behaviour that may be dependent upon self-movement cues

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

The delta family of ionotropic glutamate receptors consists of glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder