Activation of microglia by inflammation or chronic disease has profound effects on neurons and synapses. The details of this communication between the immune system and the brain are under active investigation. Common strategies to activate microglia, such as lipopolysaccharide injection or experimental autoimmune encephalomyelitis (EAE) primarily activate the peripheral immune system, triggering a complex and protracted response of the whole organism. In order to activate microglia selectively and with precise timing, we used chemogenetic activation of a Gq-DREADD expressed exclusively in microglia. This approach allowed us to study the effect of microglia on hippocampal synaptic function without the risk of direct neuronal or astrocytic activation. We used single cell electroporation of CA1 neurons and 2-photon microscopy of hippocampal slice cultures to study the impact of Gq-activated microglia on synapses. We found a sex-specific decrease in the density of excitatory synapses on CA1 pyramidal cell dendrites. We were able to prevent this effect with the BDNF scavenger TrkB-FC. Activation of Gq-DREADD in microglia in vivo significantly reduced long-term potentiation (LTP) in both sexes. Interestingly, mice with Gq-activated microglia had no problem navigating a water maze and were able to remember the location of a hidden platform days later. Taken together, our findings show that a “phantom CNS inflammation” can be induced by artificial activation of second messengers within microglia, leading to impairments in synaptic plasticity and neuronal communication. However, without activation of the peripheral immune system, spatial learning and memory are not measurably affected.