Abstract
Impaired neural synchronization is a hallmark of psychotic conditions such as schizophrenia. It has been proposed that schizophrenia-related cognitive deficits are caused by an unbalance of reciprocal inhibitory and stimulatory signaling. This supposedly leads to decreased power of induced gamma oscillations during the performance of cognitive tasks. In light of this hypothesis an efficient antipsychotic treatment should modify the connectivity and synchronization of local neural circuits. To address this issue, we investigated a model of hippocampal neuronal networks in vitro. Inhibitory and excitatory innervation of GABAergic and glutamatergic neurons was quantified using immunocytochemical markers and an automated routine to estimate network connectivity. The first generation (FGA) and second generation (SGA) antipsychotic drugs haloperidol and olanzapine, respectively, differentially modified the density of synaptic inputs. Based on the observed synapse density modifications, we developed a computational model that reliably predicted distinct changes in network activity patterns. The results of computational modeling were confirmed by spontaneous network activity measurements using the multiple electrode array (MEA) technique. When the cultures were treated with olanzapine, overall activity and synchronization were increased, whereas haloperidol had the opposite effect. We conclude that FGAs and SGAs differentially affect the balance between inhibition and excitation in hippocampal networks.
Highlights
Psychotic disorders including schizophrenia are severe diseases which affect up to 1% of the population, causing a heavy economic burden on society[1]
The dopamine hypothesis proposed that the preponderance of dopaminergic activity is central for the etiology of psychosis and dopamine receptors antagonists such as the first generation antipsychotic (FGA) haloperidol were used as primary treatments[3]
In order to understand how FGA and second generation antipsychotics (SGA) exposure modify the functional states of neural networks, we first defined the composition and survival of primary cultures of embryonic hippocampal neurons upon treatment
Summary
Psychotic disorders including schizophrenia are severe diseases which affect up to 1% of the population, causing a heavy economic burden on society[1]. The manifestation of cognitive and learning deficits in psychotic patients can be attributed to the reduced power of gamma oscillations[6] This dysfunction arises in part from a compromised excitation-inhibition balance and impaired synchronization within cortical and hippocampal neural networks[7,8,9]. The reduction of parvalbumin-containing interneurons (PV interneurons) density and the compromised formation of perineuronal nets (a special layer of extracellular matrix that regulates synaptic plasticity[16], for review see refs 17–20), correlate with altered cortical networks oscillations[6] This evidence motivated us to focus on the individual analysis of inhibitory interneurons and interacting glutamatergic cells using primary cultures of hippocampal neurons. Three weeks old cultures were examined in most experiments
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