Title: Contribution of GABAergic neurotransmission to microcircuits of amygdala and hippocampus in health and disease
Funder: Medical Research Council

Abstract: The hippocampus and the amygdala are two interconnected mammalian brain areas of fundamental importance in healthy cognitive functions such as episodic memory formation and fear learning, and directly affected in neurodegenerative diseases and psychiatric disorders. A number of neurons of the hippocampus (about 10%) and amygdala (about 30%) release the classical inhibitory neurotransmitter GABA. These cells have key roles in the correct function of neuronal circuits as exemplified by their various and profound effects on the activity of target neurons. For example, GABAergic cells set the timing of neuronal oscillations at various frequencies including 4-8 Hz theta and 30-80 Hz gamma rhythms Notably these oscillations are disrupted in several neurological diseases. The high specificity of the axonal and dendritic patterns of GABAergic cells suggests a precisely defined, highly controlled, functionally important division of labour among them. Specific types of interneurons exclusively target the dendrites of postsynaptic neurons. It is likely that the activity of such dendrite-targeting interneurons poorly influences the membrane potential in the soma and initial segment of the axon, and rather controls the generation of dendritic activity of postsynaptic cells. Furthermore, these neurons may regulate the release of glutamate from nearby excitatory fibres via a metabotropic action. At network level, GABA released from dendrite-targeting interneurons is likely to play a predominant role in shaping oscillatory patterns in the theta frequency range. Our studies in the hippocampus demonstrate that specific dendrite-targeting interneurons (neurogliaform and ivy cells) can elicit a phasic GABAergic synaptic response in postsynaptic cells, which is about 5-10 times slower than the classical fast inhibitory response. We have also found a neurogliaform cell type in the basolateral amygdala (BLA) that originates a non-classical GABAergic synaptic response. Overall, our studies suggest that certain dendrite-targeting interneurons of the amygdala and hippocampus release a GABA waveform with broad and persistent spatiotemporal profile causing postsynaptic responses with unusual slow kinetics. Furthermore, we investigate the contribution of distinct GABAergic cell types to coordinate amygdala-hippocampal interactions. To achieve this aim, we record and label neurons from the (BLA) and intercalated areas of the amygdala in rats/mice anesthetized with urethane. We also record the local field potential in the hippocampus, which reflects neuronal population synchrony and oscillations at various frequencies correlated to the animal’s behavioural state. After the electrophysiological sessions, the anatomical reconstruction of the recorded cells is performed to define their dendritic and axonal patterns, the expression of neuron type specific markers, and the preferential contacts to postsynaptic cells. By using such multidisciplinary approach, we recently discovered seven distinct neuron types in the rat amygdala. Cells’ responses to hindpaw pinches and footshocks, to mimic stimuli used in fear conditioning, also showed neuron type-specificity. My research programme is likely to significantly contribute to our understanding of the neuronal circuits underlying fear memory and extinction. Importantly, it may also lead to novel molecular targets for the pharmacological treatment of post-traumatic stress disorder and related psychiatric conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL