The ultimate aim of this laboratory is to understand how information is encoded in specific spatiotemporal activity patterns and structural configurations at the circuit, cellular, and molecular levels in the hippocampus, thereby enabling the process of memory. A major task is to find the neuronal codes of internal representations of memory items and the mapping rules between the levels of gene expression/proteins synthesis and the level of cognitive processing. Novel combinations of approaches, including multiple single-cell recording technology, patch-clamp electrophysiology, neuroanatomy/neurochemistry at the cellular and subcellular levels, and computational models are employed to test specific hypotheses about that mapping process (such as local circuit anatomy and activity-dependent short-term and long-term synaptic plasticity). Collaborations within the Institute allows the group to also incorporate gene targeting methods and behavioral learning/memory tests in their methodological repertoire.
Targeted genetic engineering: Research using in vivo and in vitro techniques has identified a range of phenomena that are suspected of playing a key role in the encoding and initial storage of information. These include long-term potentiation (LTP) and oscillatory neural activity, both being under the control of local GABAergic inhibition. Targeted genetic manipulation (including novel, drug-inducible gene-targeting techniques) are being used to generate mouse lines with a GABAergic system that has been modified in their receptor expression patterns (e.g. CB1 cannabinoid, 5-HT3, and nicotinic alpha7 receptors). The mechanisms behind any changes in the behaviour of these animals (e.g. learning and memory, anxiety, susceptibility to epilepsy) will be investigated at the network, cellular and molecular levels.
GABAergic inhibitory interneurons are known to play a major role in the generation of rhythmic (both in the theta and gamma range) and intermittent synchronous network events. Earlier work of this laboratory provided evidence that the morphological and neurochemical diversity of interneuron types is associated with distinct functional roles, i.e. perisomatic inhibitory cells control (and synchronize) the output of principal cell assemblies, whereas dendritic inhibition regulates the efficacy and plasticity of glutamatergic synaptic inputs. A third category of interneurons specialized to innervate (and synchronize) other inhibitory neurons (interneuron-selecive interneurons, or IS cells). The Freund laboratory demonstrated that local collaterals of hippocampo-septal GABAergic neurons are very extensive, and selectively innervate other interneurons, i.e. they also belong to the IS cell category. They are in an ideal position to align in phase the firing of GABAergic pacemaker units of the medial septum, as well as their target interneurons in the hippocampus. A synthesis of data about perisomatic inhibitory neurons led to the hypothesis that CCK-containing interneurons, expressing presynaptic CB1 receptors, play a key role in anxiety-like behaviours. Genetic or pharmacological interruption of CB1 receptor-mediated actions leads to anxiety, whereas blocking the new cannabinoid-sensitive receptors on glutamatergic terminals has an anxiolytic effect. The particular expertise and history of this laboratory in the morpho-functional analysis of hippocampal circuits represent sufficient ground for a continued effort - involving new molecular and behavioural approaches - to unravel the cellular and molecular bases of network operations involved in oscillations or different functional brain states, as well as in pathological activity including epilepsy and anxiety.
We demonstrated that the neurochemical characteristics and connectivity of different cell types determine their vulnerability in epilepsy and ischemia. Examination of the synaptic reorganization of dentate gyrus and cornu Ammonis in temporal lobe epileptic humans as well as in animal models revealed that, in addition to the excitatory pathways, interneurons are also able to sprout. Increased perisomatic inhibitory input was found on dentate granule cells which may participate in the hypersynchronization of the dentate gyrus enhancing the generation or maintenance of seizures. Damage to dendritic interneurons, and the presumed poor synchrony in their activity due to the loss of interneuron-selective cells, may result in an impaired dendritic inhibition and an enhanced plasticity of excitatory inputs. Abnormal inhibitory connections were observed also in the epileptic cornu Ammonis, dendritic inhibitory cells terminated on other interneurons in higher proportions then in controls. These changes were present both in sclerotic and non-sclerotic hippocampi, showing that epileptic seizures are accompained by a reviring of the network regardless of the presence or absence of principal cell loss.
