Electrophysiological Properties and Excitatory/inhibitory Balance of Parvalbumin and Somatostatin-positive Interneurons Are Altered in the Hippocampus of the Ts65Dn mouse model of Down Syndrome

Dysfunction of GABAergic interneurons during sensitive time windows plays a crucial role in the etiopathogenesis of neurodevelopmental disorders. For example, GABAergic transmission through Cl^–permeable GABA_A receptors (GABA_AR) is depolarizing in pyramidal neurons of the CA1 region of the hippocampus of the Ts65Dn mouse model of Down syndrome. This depends on the upregulation of the Cl-importer NKCC1 and leads to an impairment of synaptic plasticity and memory performance in Ts65Dn adult mice. Blocking GABAergic transmission by blocking the GABA_AR or restoring the reversal potential of GABA_AR-mediated currents by NKCC1 antagonism both rescued synaptic plasticity and memory dysfunction in Ts65Dn adult mice. However, the contribution of specific GABAergic interneurons in the hippocampal plasticity and cognitive impairment observed in Ts65Dn mice is largely unknown.

Here, we characterized parvalbumin (PV) and somatostatin (SOM)-positive interneurons in the hippocampus of 3-months-old Ts65Dn mice versus control littermates by immunohistochemistry and electrophysiological recordings on brain slices. Adult Ts65Dn mice showed a reduced number of PV interneurons and a lower expression of their perineuronal nets in the stratum pyramidale of CA1, CA3 and dentate gyrus of the hippocampus. This is suggestive of an aberrant developmental trajectory of PV neurons in Ts65Dn mice. Accordingly, Ts65Dn PV neurons showed a higher membrane time constant, wider action potentials and a lower maximal action potential frequency, typical of immature neurons. Moreover, the excitatory/inhibitory balance of those neurons was shifted towards inhibition (smaller EPSCs together with larger IPSCs, and lower frequency of mEPSCs than in controls). On the other hand, Ts65Dn SOM interneurons showed a lower membrane time constant, a higher action potential threshold, a higher action potential frequency, and lower EPSC/IPSC frequency ratio.

Altogether, our preliminary results suggest that PV neurons have a defective neurogenesis and maturation, whereas SOM neurons are hyperexcitable. This may concur to the defective hippocampal information-processing of Ts65Dn mice.