Cellular And Synaptic Physiology Of Hippocampal Interneurons

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications & trials

Abstract

In hippocampus, GABAergic local circuit inhibitory INs account for ~10-15% of the total neuronal cell population. Despite being in the minority, this diverse neuronal population serves as a major determinant of all aspects of cortical circuit function and regulation. Within the hippocampus, INs have their cell bodies scattered across all major subfields and the positioning of their somatodendritic arbors allow integration of input from a number of intrinsic and extrinsic afferent inputs. The axons of many IN subtypes largely remain local to the subfield housing their soma and dendrites, however, many form long range projections that extend beyond their original location to ramify within both cortical and subcortical structures. Their axons target well-defined narrow postsynaptic domains (i.e. soma and proximal dendrites) or can provide widespread input to large portions of target cell dendrites. This innervation of different postsynaptic cellular compartments ensures that virtually all domains of their principal neuron targets receive extensive coverage and importantly underscores that IN subtypes perform distinct roles in the hippocampal circuit. INs are primarily providers of inhibitory GABAergic synaptic input; a physiological role that utilizes Cl- influx or K+ efflux via cognate GABAA or GABAB receptor activation respectively, to transiently hyperpolarize or shunt the cell membrane away from action potential threshold. They play major roles in not only the regulation of single cell excitability, but provide well-timed inhibitory input that dictates the temporal window for synaptic excitation, and subsequent action potential initiation, thus shaping the timing of afferent and efferent information flow. In addition, they harness and synchronize both local and distributed cortical circuits to facilitate oscillatory activity across broad frequency domains. Indeed, several developmentally regulated neural circuit disorders such as epilepsy, schizophrenia and autism are likely associated with deficits in the numbers and function of distinct IN cohorts. For all of these reasons INs have recently become the intense focus of investigators drawn from a wide variety of backgrounds. Over the last year our research has focused on three main aspects of IN function: (1) We continued our study of glutamatergic and GABAergic synaptic transmission made onto, and from INs and their downstream targets, within the hippocampal and cortical formations. (2) We have capitalized and expanded our research using genetic and viral approaches to examine the development of specific cohorts of medial- and caudal-ganglionic eminence derived INs and their roles in both nascent- and mature-circuits. (3) As part of a multi-institute consortium we have expanded our studies to consider evolutionary conservation or diversity of principal neuron and interneuron function and in collaboration with NINDS neurosurgery, surgically resected human hippocampal and cortical tissue. This multiparametric research approach to circuit development and function has been extremely fruitful and is in my mind a perfect example of why our research strategy is well suited for the intramural environment. Having the flexibility to pursue this line of research would not have been possible without the support and collaborative nature of the NIH intramural program. 1. Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development Within adult rodent hippocampus, opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), disinhibiting local microcircuits. However, it is unknown whether this disinhibitory motif is conserved across cortical regions, species, or development. We observed that PV-IN-mediated inhibition is robustly suppressed by opioids in HPC proper but not primary neocortex in mice and non-human primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif is established in early development when PV-INs and opioids regulate early population activity. Morphine pretreatment partially occludes this acute opioid-mediated suppression, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Our findings demonstrate that PV-INs exhibit divergent opioid sensitivity across brain regions, which is remarkably conserved over evolution, and highlight the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development. 2. An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the telencephalic interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic interneurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy. 3. Local Regulation of Striatal Dopamine Release Shifts from Predominantly Cholinergic in Mice to GABAergic in Macaques Dopamine critically regulates neuronal excitability and promotes synaptic plasticity in the striatum, thereby shaping network connectivity and influencing behavior. These functions establish dopamine as a key neuromodulator, whose release properties have been well studied in rodents but remain understudied in nonhuman primates. This study aims to close this gap by investigating the properties of dopamine release in macaque striatum and comparing/contrasting them to better-characterized mouse striatum, using ex vivo brain slices from male and female animals. Using combined electrochemical techniques and photometry with fluorescent dopamine sensors, we found that evoked dopamine signals have smaller amplitudes in macaques compared with those in mice. Interestingly, cholinergic-dependent dopamine release, which accounts for two-thirds of evoked dopamine release in mouse slices, is significantly reduced in macaques, providing a potential mechanistic underpinning for the observed species difference. In macaques, only nicotinic receptors with alpha-6 subunits contribute to evoked dopamine release, whereas in mice, both alpha-6 and non-alpha6-containing receptors are involved. We also identified robust potentiation of dopamine release in both species when GABAA and GABAB receptors were blocked. This potentiation was stronger in macaques, with an average increase of 50%, compared with 15% in mice. Together, these results suggest that dopamine release in macaque is under stronger GABA-mediated inhibition and that weaker cholinergic-mediated dopamine release may account for the smaller amplitude of evoked dopamine signals in macaque slices.