Editors' ChoiceNeuroscience

Making More Inhibitory Connections

Sci. Signal.  12 Nov 2013:
Vol. 6, Issue 301, pp. ec275
DOI: 10.1126/scisignal.2004899

Learning and memory are represented at the cellular level through precise modulation of neuronal output in part by regulation of the number, strength, and topology of inhibitory synaptic inputs. Consistent with previous work done in cell culture, Bloodgood et al. show that the activity-dependent transcription factor NPAS4 is required for the distribution of inhibitory synapses on CA1 pyramidal neurons in the hippocampus of mice maintained in an enriched environment (EE) that promotes learning. Mice maintained in an EE or injected with kainic acid (KA), which is used to induce neuronal hyperactivation, had increased NPAS4 in the hippocampus relative to mice maintained in the standard environment (SE) or injected with the vehicle solution alone. NPAS4 knockout (KO) pyramidal neurons [identified by the coexpression of green fluorescent protein (GFP)] showed less frequent and smaller miniature inhibitory postsynaptic currents (mIPSCs) relative to neighboring wild-type (GFP-negative) neurons in EE- but not SE-maintained mice. Inhibitory neurons in different layers of the CA1 region synapse onto pyramidal neurons. The rise times of evoked inhibitory postsynaptic currents derived from stimulation of various layers of the CA1 were variably impacted by NPAS4-KO, indicating that NPAS4 was not universally required for modulation of all inhibitory synapses on pyramidal neurons. NPAS4-KO did not affect the number or morphology of dendrites or presynaptic release of inhibitory neurotransmitters but rather reduced the number of dendritic and increased the number of somatic inhibitory synapses on pyramidal neurons. NPAS4 bound to the enhancer region of Bdnf and was required for its transcription in the hippocampus of KA-injected mice. Conditional knockout of Bdnf in a subset of neurons in the CA1 region of mice reduced the amplitude of mIPSCs on the BDNF-KO neurons when the mice were maintained in an EE or injected with KA. Thus, NPAS4 is required for changes in the distribution of inhibitory synapses in response to neuronal excitation, likely through regulation of Bdnf and other genes, and could play a role in learning and memory (see Sylwestrak and Scheiffele).

B. L. Bloodgood, N. Sharma, H. A. Browne, A. Z. Trepman, M. E. Greenberg, The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503, 121–125 (2013). [PubMed]

E. Sylwestrak, P. Scheiffele, Sculpting neuronal connectivity. Nature 503, 42–43 (2013). [PubMed]