Optogenetic activation of mesencephalic projections to the nucleus accumbens shell impairs probabilistic reversal learning by disrupting learning from negative reinforcement.

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning.

Control of sustained attention and impulsivity by G-protein signalling in parvalbumin interneurons of the anterior cingulate cortex.

The anterior cingulate cortex (ACC) has been implicated in attention deficit hyperactivity disorder (ADHD). More specifically, an appropriate balance of excitatory and inhibitory activity in the ACC may be critical for the control of impulsivity, hyperactivity, and sustained attention which are centrally affected in ADHD. Hence, pharmacological augmentation of parvalbumin- (PV) or somatostatin-positive (Sst) inhibitory ACC interneurons could be a potential treatment strategy.

Control of impulsivity by G-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex.

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity.

Suppression of Parvalbumin Interneuron Activity in the Prefrontal Cortex Recapitulates Features of Impaired Excitatory/Inhibitory Balance and Sensory Processing in Schizophrenia.

Accumulating evidence supports parvalbumin expressing inhibitory interneuron (PV IN) dysfunction in the prefrontal cortex as a cause for cognitive impairment associated with schizophrenia (CIAS). PV IN decreased activity is suggested to be the culprit for many of the EEG deficits measured in patients, which correlate with deficits in working memory (WM), cognitive flexibility and attention. In the last few decades, CIAS has been recognized as a heavy burden on the quality of life of patients with schizophrenia, but little progress has been made in finding new treatment options.

Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice.

Muscarinic Designer Receptors Exclusively Activated by Designer Drugs (DREADD) gated by clozapine-N-oxide (CNO) allow selective G-protein cascade activation in genetically specified cell-types in vivo. Here we compare the pharmacokinetics, off-target effects and efficacy of CNO, clozapine (CLZ) and compound 21 (Cmpd-21) at the inhibitory DREADD human Gi-coupled M4 muscarinic receptor (hM4Di). The half maximal effective concentration (EC) of CLZ was substantially lower (0.

Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.

Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons.

Transgenic overexpression of the type I isoform of neuregulin 1 affects working memory and hippocampal oscillations but not long-term potentiation.

Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1(tg-type I)) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes.

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue.

Priming of hippocampal population bursts by individual perisomatic-targeting interneurons.

Hippocampal population bursts ("sharp wave-ripples") occur during rest and slow-wave sleep and are thought to be important for memory consolidation. The cellular mechanisms involved are incompletely understood. Here we investigated the cellular mechanisms underlying the initiation of sharp waves using a hippocampal slice model.

Cell type-specific long-term plasticity at glutamatergic synapses onto hippocampal interneurons expressing either parvalbumin or CB1 cannabinoid receptor.

Different GABAergic interneuron types have specific roles in hippocampal function, and anatomical as well as physiological features vary greatly between interneuron classes. Long-term plasticity of interneurons has mostly been studied in unidentified GABAergic cells and is known to be very heterogeneous. Here we tested whether cell type-specific plasticity properties in distinct GABAergic interneuron types might underlie this heterogeneity.

Role of ionotropic glutamate receptors in long-term potentiation in rat hippocampal CA1 oriens-lacunosum moleculare interneurons.

Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This "anti-Hebbian" form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known.